Substituted Fused Pyrimidine Compounds

ABSTRACT

The present invention discloses substituted fused pyrimidine compounds of formula (I), their tautomers, polymorphs, stereoisomers, solvates, pharmaceutically acceptable salts, or pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by adenosine receptor (AR) activity. The compounds of the present invention are useful in the treatment, prevention or suppression of diseases and disorders that may be susceptible to improvement by antagonism of the adenosine receptor, such as asthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema, allergic diseases, inflammation, reperfusion injury, myocardial ischemia, atherosclerosis, hypertension, congestive heart failure, retinopathy, diabetes mellitus, obesity, inflammatory gastrointestinal tract disorders, and/or autoimmune diseases.

FIELD OF THE INVENTION

The present invention relates to a series of novel substituted fusedpyrimidine compounds, their tautomers, polymorphs, stereoisomers,prodrugs, solvates, pharmaceutically acceptable salts, pharmaceuticalcompositions containing them and methods of treating conditions anddiseases that are mediated by adenosine receptor (AR) activity. Thesecompounds are useful in the treatment, prevention or suppression ofdiseases and disorders that may be susceptible to improvement byantagonism of the adenosine receptor, such as asthma, chronicobstructive pulmonary disorder, angiogenesis, pulmonary fibrosis,emphysema, allergic diseases, inflammation, reperfusion injury,myocardial ischemia, atherosclerosis, hypertension, congestive heartfailure, retinopathy, diabetes mellitus, obesity, inflammatorygastrointestinal tract disorders, neurodegenerative disorders and/orautoimmune diseases.

BACKGROUND OF THE INVENTION

Adenosine is known to be an endogenous modulator of a number ofphysiological functions and these are mediated by the interaction withdifferent membrane specific receptors which belong to the family ofreceptors coupled with G proteins. Adenosine exerts effects incardiovascular, central nervous, respiratory systems, kidney, adiposeand platelets. Recent advances in molecular biology coupled with severalpharmacological studies have lead to identification of at least foursubtypes of adenosine receptors, A₁, A_(2B), A_(2b) and A₃. The A₁ andA₃ receptors down-regulate cellular cAMP levels through their couplingto G protein, which inhibit adenylate cyclase. In contrast, A_(2A) andA_(2B) receptors couple to G protein that activate adenylate cyclase andincrease intracellular levels of cAMP.

Advances in understanding the role of adenosine and its receptors inphysiology and pathophysiology as well as new developments in medicinalchemistry of these receptors have identified potential therapeutic areasfor drug development. With the combination of pharmacological data,using selective ligands and genetically modified mice, importantprogress has been made toward an understanding of the role of ARs in avariety of diseases, such as inflammatory conditions, sepsis, heartattack, ischemia-reperfusion injury, vascular injury, spinal cordinjury, chronic obstructive pulmonary disease (COPD), asthma, diabetes,obesity, inflammatory bowel disease, retinopathy, and Parkinson'sDisease (PD).

In the central nervous system, A_(2a) antagonists can haveantidepressant properties and stimulate cognitive functions. There isfairly convincing prospective epidemiological evidence of a protectiveeffect of caffeine against Parkinson's disease. Moreover, data has shownthat A_(2a) receptors density is very high in the basal ganglia, knownto be important in the control of movement. Hence, selective A_(2a)antagonists can improve motor impairment due to neurodegenerativediseases such as Parkinson's disease (Trends Pharmacol. Sci. 1997, 18,338-344), senile dementia as in Alzheimer's disease, psychoses, strokeand in the treatment of cerebral ischaemia (Life Sci. 1994, 55, 61-65).A_(2a) antagonists may also be employed for the treatment or managementof attention related disorders such as attention deficit disorder andattention deficit hyperactivity disorder, extra pyramidal syndrome,e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia,and disorders of abnormal movement such as restless leg syndrome andperiodic limb movement in sleep. Several of these indications have beendisclosed in patent applications (eg. WO 02/055083, WO 05/044245 and WO06/132275). Adenosine A_(2a) antagonists are also useful agents for thetreatment of amyotrophic lateral sclerosis, cirrhosis, and fibrosis andfatty liver (US2007037033, WO 01/058241). A_(2a) receptor antagonistsare also useful for the mitigation of addictive behavior (WO 06/009698)and for the treatment and prevention of dermal fibrosis in diseases suchas scleroderma (Arthritis & Rheumatism, 54(8), 2632-2642, 2006).

PD is a progressive, incurable disorder with no definite preventivetreatment, although drugs are available to alleviate the symptoms and/orslow down the progress of the disease. Among the various strategies, A2AAR blockers are considered a potential approach to treatment of thedisease.

Within the brain A2A ARs are richly expressed in the striatum, nucleusaccumbens, and olfactory tubercle. A coexpression of A2A with D2dopamine receptors has been reported in the GABAergic striatopallidalneurons where adenosine and dopamine agonists exert antagonistic effectsin the regulation of locomotor activity. Activation of A2A ARs instriatopallidal neurons decreases the affinity of D2 receptors fordopamine, antagonizing the effects of D2 receptors. The negativeinteraction between A2A and D2 receptors is at the basis of the use ofA2A antagonists as a novel therapeutic approach in the treatment of PD.(Pharmacol. Ther. 2005, 105, 267). The recent discovery that the A2A canform functional heteromeric receptor complexes with otherGprotein-coupled receptors such as D2 and the mGlu5 receptors has alsosuggested new opportunities for the potential of A2A antagonists in PD.(J. Mol. Neurosci. 2005, 26, 209).

A2A receptors may be beneficial for the treatment or prevention ofdisorders such as a movement disorder, for example, Parkinson's diseaseor progressive supernuclear palsy, Restless leg syndrome, nocturnalmyoclonus, cerebral ischaemia, Huntington's disease, multiple systematrophy, corticobasal degeneration, Wilsons disease or other disordersof basal ganglia which results in dyskinesias. See for exampleWO200013682, WO200012409, WO2009156737, WO200911442, WO2008121748,WO2001092264, WO2007038284, WO2008002596, WO2009111449, WO2009111442,WO2008121748, WO2009156737, WO2003022283, WO2005044245, WO2007038212.

Adenosine signaling is known to serve apoptotic, angiogenic andpro-inflammatory functions and might be relevant to the pathogenesis ofasthma and chronic obstructive pulmonary disease (Trends inPharmacological Sciences, Vol. 24, No. 8, August 2003). Extracellularadenosine acts as a local modulator with a generally cytoprotectivefunction in the body. Its effects on tissue protection and repair fallinto four categories: increasing the ratio of oxygen supply to demand;protecting against ischaemic damage by cell conditioning; triggeringanti-inflammatory responses; and the promotion of angiogenesis. TheA_(2B) adenosine receptor subtype (see Feoktistov, I., Biaggioni, I.Pharmacol. Rev. 1997, 49, 381-402) has been identified in a variety ofhuman and murine tissues and is involved in the regulation of vasculartone, smooth muscle growth, angiogenesis, hepatic glucose production,bowel movement, intestinal secretion, and mast cell degranulation.A_(2B) receptors have been implicated in mast cell activation andasthma, control of vascular tone, cardiac myocyte contractility, cellgrowth and gene expression, vasodilation, regulation of cell growth,intestinal function, and modulation of neurosecretion (PharmacologicalReviews Vol. 49, No. 4).

A_(2B) receptors modulate mast cell function. Adenosine activatesadenylate cyclase and protein kinase C, and potentiates stimulatedmediator release in mouse bone marrow derived mast cells. (TiPS—April1998 (Vol. 19)). Activation of A_(2B) receptors in HMC-1 augments IL-8release and potentiates PMA-induced secretion of IL-8. Thus, adenosinewould contribute to the asthmatic response by acting on the mast cell toenhance the release of proinflammatory mediators. (PulmonaryPharmacology & Therapeutics 1999, 12, 111-114). In COPD, transformationof pulmonary fibroblasts into myofibroblasts is considered a majormechanism. Activation of the A_(2B) AR is involved in this process.Selective A_(2B) antagonists are expected to have beneficial effect onpulmonary fibrosis (Curr. Drug Targets, 2006, 7, 699-706; Am. J. Resper.Cell. Mol. Biol., 2005, 32, 228). A_(2B) antagonists can be used aswound healing agents. Activation of the A_(2B) AR promotes angiogenesisby increasing the release of angiogenic factors and A_(2B) antagonistsare useful to block angiogenesis (Circ. Res., 2002, 90, 531-538). A_(2B)AR may be involved in the inhibition cardiac fibroblast (CF)proliferation (Am. J. Physiol. Heart Circ. Physiol., 2004, 287,H2478-H2486). Adenosine stimulates Cl− secretion in the intestinalepithelia pointing towards a possible treatment for cystic fibrosispatients with CFTR mutation (Am. J. Respir. Cell Mol. Biol., 2008, 39,190-197). High affinity A_(2B) antagonists are effective in hot platemodel suggestive of the role of A_(2B) in nociception and can be used aspotential analgesic agents (The J. of Pharmacol. and Exp. Ther., 2004,308, 358-366).

A_(2B) receptor is involved in release of IL-6. Increasing evidencesuggests that IL-6 plays a role in Alzheimer's disease in the context ofinflammatory process associated with disease. Hence A_(2B) receptorantagonist might be useful for Alzheimer's disease.

The A_(2B) ARs are involved in the stimulation of nitric oxideproduction during Na⁺-linked glucose or glutamine absorption. They areinvolved in glucose production in hepatocytes upon agonist stimulation.A_(2B)-receptor antagonists showed an anti-diabetic potential mainly byincreasing plasma insulin levels under conditions when the adenosinetonus was elevated in-vivo and increased insulin release in-vitro (JPharm. Pharmacol. 2006 December; 58(12):1639-45). Thus A_(2B)antagonists may serve as a novel target for the treatment of thismetabolic disease.

It has been demonstrated that adenosine activation of the A_(2B)adenosine receptor increase cAMP accumulation, cell proliferation andVEGF expression in human retinal endothelial cells. Activation ofA_(2B)AdoR increased vascular endothelial cell growth factor mRNA andprotein expression in human retinal endothelial cells. Adenosine alsohas a synergistic effect with VEGF on retinal endothelial cellproliferation and capillary morphogenesis in vitro. Such activity isnecessary in healing wounds, but the hyperproliferation of endothelialcells promotes diabetic retinopathy. Also, an undesirable increase inblood vessels occurs in neoplasia. Accordingly, inhibition of binding ofadenosine to A_(2B) receptors in the endothelium will alleviate orprevent hypervasculation, thus preventing retinopathy and inhibitingtumor formation.

In view of the physiological effects mediated by adenosine receptor,several A_(2B) receptor antagonists have been recently disclosed for thetreatment or prevention of asthma, bronchoconstriction, allergicdiseases, hypertension, atherosclerosis, reperfusion injury, myocardialischemia, retinopathy, inflammation, gastrointestinal tract disorders,cell proliferation diseases and/or diabetes mellitus. See for exampleWO2008002902, WO2007149277, WO2007017096, WO2007109547, WO2006091896,WO2006015357, WO2005042534, WO2005021548, WO2004106337, WO2003000694,WO2003082873, WO2003006465, WO2003053361, WO2003002566, WO2003063800,WO2003042214, WO2003035639, EP1283056, WO200073307, WO2000125210,WO2000073307, US20050119287, US20060281927.

It has now been found that compounds of the present invention are potentantagonists of the A_(2B) adenosine receptor and can therefore be usedin the treatment of the diseases mentioned herein above.

Under normal physiological conditions, A₁ ARs are quiescent; however, A₁ARs are upregulated in conditions of stress, such as ischaemia, and inconditions of inflammation, typified by the inflammatory airwayinvolvement in human asthmatics. A₁ ARs are upregulated in airwayepithelium and bronchial smooth muscle in human asthmatics. A₁ ARs havebeen described on a number of different human cell types that areimportant in the pathophysiology of asthma, including APCs, human airwayepithelial and bronchial smooth muscle cells, lymphocytes, mast cells,neutrophils, monocytes, macrophages, fibroblasts and endothelial cells.Activation of A₁ ARs on these different cell types induces the releaseof mediators and cytokines that lead to airway hyperreactivity,inflammation and airway remodelling. Activation of A₁ ARs on humanasthmatic bronchial tissue produces bronchoconstriction. On human airwayepithelial cells, activation of A₁ ARs causes an increase in expressionof the MUC 2 gene responsible for mucus hypersecretion. Moreover,activation of A₁ ARs on a number of different human cells producespro-inflammatory effects. Taken together, these effects of A₁ ARs inhumans suggest that the A₁ AR antagonists could play potentialtherapeutic role in inflammatory diseases (C N Wilson, British J. ofPharm., 2008, 155, 475-86 and references cited therein). A₁ ARantagonists have been shown to have efficacy in rodent models of asthmaand inflammation ((J. Pharmacol. Exp. Ther. 315, 329-336, 2005; Eur. J.Pharmacol., 551, 116-124, 2006).

A₁ antagonists have also been shown to have therapeutic potential indiseases such as hypertension, congestive heart failure where underlyingmechanism is diuresis. There are several compounds in development forthese indications (J. Am. Soc. Nephrol. 10, 714-720, 1999; Circulation,105, 1348-1353, 2002; J. Pharmacol. Exp. Ther. 308, 846-856, 2004).

A₁ AR antagonists are reported to reduce infarct size. It has beensuggested that the ability of A₁ AR antagonists to reduce the infarctsize is also mediated by antagonism at A_(2B) AR (Circulation, 1996, 9,94; J. Pharmacol. Exp. Ther., 2000, 292, 3, 929-938).

Activation of A₃ ARs induces the release of preformed mediators frombasophils and produces bronchoconstriction, eosinophil migration intoairways and mucus hypersecretion in animals, A₃ AR antagonists have beenrecommended for development as anti-asthma drugs (Fishman andBar-Yehuda, 2003; Nadeem and Mustafa, 2006). A₃ AR antagonists have alsobeen shown to play therapeutic role in various diseases includingcardio-protection (Vasc. Pharmacol., 2005, 42, 271; J. Pharm. Exp.Ther., 2006, 319, 1200) and cancer (WO200010391).

Since several ARs have been implicated in asthma/COPD diseasespathophysiology, a pan AR antagonist may have therapeutic advantage.

It has now been found that some of the compounds of the presentinvention are non-selective antagonists of ARs and can therefore be usedin the treatment of above mentioned diseases.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I),

or its tautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein

-   -   Y is selected from N or CR; R is selected from H, hydroxy,        alkoxy, alkyl, or aryl;    -   R¹ is selected from a group consisting of alkyl, alkenyl and        alkynyl, wherein one or more methylene groups are optionally        replaced by hetero atoms or group selected from —O—, —S(O)p-,        —N(R^(a))—, or —C(O) provided that the heteroatom is not        adjacent to N in the ring; p is selected from 0, 1 or 2;        -   wherein alkyl, alkenyl and alkynyl are unsubstituted or            substituted independently with alkoxy, acyl, acylamino,            acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, haloalkyl,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, aminocarbonylamino,            hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(a)R^(a),            —NR^(a)S(O)₂R^(a), or —S(O)_(p)R^(a);        -   R² is selected from a group consisting of hydrogen, halogen,            cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl,            alkynyl, hydroxyalkyl, carboxyalkyl, halo alkyl,            haloalkyloxy, alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b),            cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl,            aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            heteroaryl, heteroarylalkyl and heteroaryloxy;            -   wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl,                cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl,                arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl,                heterocyclyloxy, heteroaryl, heteroarylalkyl,                heteroaryloxy and R^(b) are unsubstituted or substituted                independently with alkyl, alkenyl, alkynyl, alkoxy,                acyl, acylamino, acyloxy, nitro, amino, monoalkylamino,                dialkylamino, hydroxyamino, alkoxyamino,                aminocarbonylamino, azido, cyano, halogen, hydroxy,                hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,                carboxyalkyl, —SO₃H, arylamino, cycloalkylamino,                heteroarylamino, heterocyclylamino, aminocarbonyl,                alkoxycarbonylamino, cycloalkyl, cycloalkyloxy,                cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy,                heterocyclyl, heterocyclyloxy, —S(O)₂NR^(c)R^(c),                —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);                -   wherein each substituent is unsubstituted or                    substituted with 1, 2, or 3 substituents                    independently selected from alkyl, carboxy,                    carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,                    halogen, haloalkyl, haloalkoxy, amino, substituted                    amino, cyano or —S(O)_(p)R^(d);    -   R³ is selected from a group consisting of hydrogen, alkyl,        alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,        aryl, arylalkyl, heteroaryl and heteroarylalkyl;        -   wherein alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,            cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and            heteroarylalkyl are unsubstituted or substituted            independently with alkyl, alkenyl, alkynyl, alkoxy,            cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SO₃H,            aryl, aryloxy, cycloalkyloxy, heteroaryl,            aminocarbonylamino, heteroaryloxy, heterocyclyl,            heterocyclyloxy, hydroxyamino, alkoxyamino, nitro,            S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyd,                alkoxy, halogen, haloalkyl, haloalkoxy, amino,                substituted amino, cyano or —S(O)_(p)R^(d);    -   X is either an optionally substituted arylene or an optionally        substituted heteroarylene;    -   A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(p)—, —N(R^(b))—, or —C(O)—;        -   wherein alkylene, alkenylene, and alkynylene are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,            acylamino, acyloxy, amino, monoalkylamino, dialkylamino,            arylamino, cycloalkylamino, heteroarylamino,            heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,            azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,            thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl,            carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H, aryl, aryloxy,            cycloalkyloxy, heteroaryl, aminocarbonylamino,            heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino,            alkoxyamino, nitro, S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or            —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, CF₃, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or        heteroaryl;        -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,            cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,            aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl,            heteroarylalkyl, aminocarbonylamino, heteroaryloxy,            heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(b)R^(b),            —NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                haloalkoxy, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   R^(a) is independently selected from the group consisting of        hydrogen and alkyl;    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   R^(c) is selected from hydrogen, alkyl, aryl, heteroaryl or        heterocyclyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

The present invention also provides methods of treating conditions anddiseases that are mediated by adenosine receptor activity.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the structural formulae given herein and throughout the presentdisclosure, the following terms have the indicated meaning, unlessspecifically stated otherwise.

The term “optionally substituted” as used herein means that the group inquestion is either unsubstituted or substituted with one or more of thesubstituents specified. When the group in question is substituted withmore than one substituent, the substituent may be same or different.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl,tetradecyl, and the like.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6carbon atoms. This term is exemplified by groups such as methylene(—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂—and —CH(CH₃)CH₂—) and the like.

The term “substituted alkyl” or “substituted alkylene” refers to: 1) analkyl group or alkylene group as defined above, having 1, 2, 3, 4 or 5substituents, preferably 1, 2 or 3 substituents, selected from the groupconsisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino,heteroarylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,carboxyalkyl, —SO₃H, aryl, aryloxy, heteroaryl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino,nitro, —S(O)₂NR^(a)R^(a), NR^(a)S(O)₂R^(a) and —S(O)_(p)R^(b), whereeach R^(a) is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl;heterocyclyloxy where R^(b) is hydrogen, alkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(p)R^(c), where R^(a) is alkyl, aryl, or heteroaryl and p is 0, 1or 2;

or 2) an alkyl group or alkylene group as defined above that isinterrupted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms independentlyselected from oxygen, sulfur and NR^(d), where R^(d) is selected fromhydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl andheterocyclyl, carbonylalkyl, carboxyester, carboxyamide and sulfonyl.All substituents may be optionally further substituted by alkyl, alkoxy,halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(p)R^(c), inwhich R^(c) is alkyl, aryl, or heteroaryl and p is 0, 1, or 2;or 3) an alkyl or alkylene as defined above that has 1, 2, 3, 4 or 5substituents as defined above, as well as interrupted by 1, 2, 3, 4, 5,6, 7, 8, 9 or 10 atoms as defined above.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, morepreferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even morepreferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 2, 3, 4, 5 or 6double bond (vinyl), preferably 1 double bond. Preferred alkenyl groupsinclude ethenyl or vinyl (—CH═CH₂), 1-propylene or allyl (—CH₂CH═CH₂),isopropylene (—C(CH₃)═CH₂), bicyclo[2.2.1]heptene, and the like.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, morepreferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even morepreferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 3, 4, 5 or 6double bond (vinyl), preferably 1 double bond.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,thiocarbonyl, carboxy, carboxyalkyl, —SO₃H, aryl, aryloxy, heteroaryl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy,hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(a)R^(a), —NR^(a)S(O)₂R^(a)and —S(O)_(p)R^(b) where each R^(a) is independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl andheterocyclylalkyl; heterocyclyloxy where R^(b) is alkyl, aryl,heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents selected from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(p)R^(c), where R^(c) isalkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4,5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or6 carbon atoms and having 1, 2, 3, 4, 5 or 6 sites of acetylene (triplebond) unsaturation, preferably 1 triple bond. Preferred alkynyl groupsinclude ethynyl, (—C≡CH), propargyl (or prop-1-yn-3-yl, —CH₂C≡CH),homopropargyl (or but-1-yn-4-yl, —CH₂CH₂C≡CH) and the like.

The term “alkynylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, morepreferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even morepreferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 3, 4, 5 or 6 sitesof acetylene (triple bond) unsaturation, preferably 1 triple bond.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, —SO₃H, aryl,aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(a)R^(a),—NR^(a)S(O)₂R^(a) and —S(O)_(p)R^(b), where each R^(a) is independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,heterocyclyl and heterocyclylalkyl; heterocyclyloxy where R^(b) isalkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents selected from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(p)R^(c) where R^(c) isalkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term “cycloalkyl” refers to carbocyclic groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed ringswhich may be partially unsaturated. Such cycloalkyl groups include, byway of example, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl,bicyclo[2.2.1]heptane, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl,(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to whichis fused an aryl group, for example indane, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups having 1,2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents,selected from the group consisting of alkyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl,aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino,nitro, —C(O)R and —S(O)_(p)R^(b), where R is hydrogen, hydroxyl, alkoxy,alkyl and cycloalkyl, heterocyclyloxy where R^(b) is alkyl, aryl,heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents selected from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(p)R^(c), where R^(c) isalkyl, aryl, or heteroaryl and p is 0, 1 or 2.

“Halo” or “Halogen”, alone or in combination with any other term meanshalogens such as chloro (Cl), fluoro (F), bromo (Br) and iodo (I).

“Haloalkyl” refers to a straight chain or branched chain haloalkyl groupwith 1 to 6 carbon atoms. The alkyl group may be partly or totallyhalogenated. Representative examples of haloalkyl groups include but arenot limited to fluoromethyl, chloromethyl, bromomethyl, difluoromethyl,dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl,2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,3-fluoropropyl, 3-chloropropyl, 3-bromopropyl and the like.

The term “alkoxy” refers to the group R′″—O—, where R′″ is optionallysubstituted alkyl or optionally substituted cycloalkyl, or optionallysubstituted alkenyl or optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Representative examples of alkoxygroups include but are not limited to methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, trifluoromethoxy, and the like.

The term “aminocarbonyl” refers to the group —C(O)NR′R′ where each R′ isindependently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or both R′groups are joined to form a heterocyclic group (e.g. morpholino). Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(p)R^(c), where R^(c) is alkyl,aryl, or heteroaryl and p is 0, 1 or 2.

The term “acylamino” refers to the group —NR″C(O)R″ where each R″ isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(p)R^(c), where R^(c) is alkyl,aryl, or heteroaryl and p is 0, 1 or 2.

The term “acyloxy” refers to the groups —OC(O)-alkyl, —OC(O)-cycloalkyl,—OC(O)-aryl, —OC(O)-heteroaryl, and —OC(O)-heterocyclyl. Unlessotherwise constrained by the definition, all substituents may beoptionally further substituted by alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, or —S(O)_(p)R^(c), where R^(c) is alkyl, aryl, or heteroaryl andp is 0, 1 or 2.

“Alkoxyalkyl” refers to alkyl groups as defined above wherein at leastone of the hydrogen atoms of the alkyl group is replaced by an alkoxygroup as defined above. Representative examples of alkoxyalkyl groupsinclude but are not limited to methoxymethyl, methoxyethyl, ethoxymethyland the like.

“Aryloxyalkyl” refers to the group -alkyl-O-aryl. Representativeexamples of aryloxyalkyl include but are not limited to phenoxymethyl,naphthyloxymethyl, phenoxyethyl, naphthyloxyethyl and the like.

“Di alkylamino” refers to an amino group, to which two same or differentstraight chain or branched chain alkyl groups with 1 to 6 carbon atomsare bound. Representative examples of di alkylamino include but are notlimited to dimethylamino, diethylamino, methylethylamino, dipropylamino,dibutylamino and the like.

“Cycloalkylalkyl” refers to an alkyl radical as defined above which issubstituted by a cycloalkyl radical as defined above. Representativeexamples of cycloalkylalkyl include but are not limited tocyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylbutyl and the like.

“Aminoalkyl” refers to an amino group that is attached to (C₁₋₆)alkyleneas defined herein. Representative examples of aminoalkyl include but arenot limited to aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl,and the like. The amino moiety of aminoalkyl may be substituted once ortwice with alkyl to provide alkylaminoalkyl and dialkylaminoalkylrespectively. Representative examples of alkylaminoalkyl include but arenot limited to methylaminomethyl, methylaminoethyl, methylaminopropyl,ethylaminoethyl and the like. Representative examples ofdialkylaminoalkyl include but are not limited to dimethylaminomethyl,dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl andthe like.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g. phenyl) or multiple rings (e.g.biphenyl), or multiple condensed (fused) rings (e.g. naphthyl oranthranyl). Preferred aryls include phenyl, naphthyl and the like.

The term “arylene” refers to a diradical of an aryl group as definedabove. This term is exemplified by groups such as 1,4-phenylene,1,3-phenylene, 1,2-phenylene, 1,4′-biphenylene, and the like.

Unless otherwise constrained the aryl or arylene groups may optionallybe substituted with 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3substituents, selected from the group consisting of alkyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,carboxy, carboxyalkyl, —SO₃H, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy,hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(a)R^(a), —NR^(a)S(O)₂R^(a)and —S(O)_(p)R^(b) where each R^(a) is independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl andheterocyclylalkyl; where R^(b) is hydrogen, alkyl, aryl, heterocyclyl orheteroaryl and p is 0, 1 or 2. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, and —S(O)_(p)R^(c) where R^(c) is hydrogen, alkyl, aryl, orheteroaryl and p is 0, 1 or 2.

The term “arylalkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein.

“Optionally substituted arylalkyl” refers to an optionally substitutedaryl group covalently linked to an optionally substituted alkylenegroup. Such arylalkyl groups are exemplified by benzyl, phenethyl,naphthylmethyl, and the like.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above.

The term “arylthio” refers to the group —S-aryl, where aryl is asdefined herein including optionally substituted aryl groups as alsodefined above.

The term “substituted amino” refers to the group —NR′R′ where each R′ isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, carboxyalkyl, alkoxycarbonyl, aryl, heteroaryl andheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(p)R^(c), where R^(c) is alkyl, aryl, or heteroaryl and p is 0, 1or 2.

The term “carboxyalkyl” refers to the groups -alkylene-C(O)OH.

The term “alkylcarboxyalkyl” refers to the groups -alkylene-C(O)OR^(d)where R^(d) is alkyl, cycloalkyl, where alkyl, cycloalkyl are as definedherein, and may be optionally further substituted by alkyl, halogen,CF₃, amino, substituted amino, cyano, or —S(O)_(p)R^(c), in which R^(c)is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term “heteroaryl” refers to an aromatic cyclic group having 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms and 1, 2, 3 or4 heteroatoms selected from oxygen, nitrogen and sulfur within at leastone ring. Such heteroaryl groups can have a single ring (e.g. pyridyl orfuryl) or multiple condensed rings (e.g. indolizinyl, benzothiazolyl, orbenzothienyl). Examples of heteroaryls include, but are not limited to,[1,2,4] oxadiazole, [1,3,4] oxadiazole, [1,2,4] thiadiazole, [1,3,4]thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline,quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,acridine, phenanthroline, isothiazole, phenazine, isoxazole,phenoxazine, phenothiazine, furan, thiophene, oxazole, thiazole,triazole, triazine and the like.

The term “heteroarylene” refers to a diradical of a heteroaryl group asdefined above.

Unless otherwise constrained the heteroaryl or heterarylene groups canbe optionally substituted with 1, 2, 3, 4 or 5 substituents, preferably1, 2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, thiocarbonyl, carboxy, carboxyalkyl, —SO₃H, aryl,aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(a)R^(a),—NR^(a)S(O)₂R^(a) and —S(O)_(p)R^(b), where each R^(a) is independentlyselected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,heterocyclyl and heterocyclylalkyl; where R^(b) is hydrogen, alkyl,aryl, heterocyclyl or heteroaryl, and p is 0, 1 or 2. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1-3 substituents selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R^(c), where R^(c) is alkyl,aryl, or heteroaryl and n is 0, 1 or 2.

The term “heteroarylalkyl” refers to a heteroaryl group covalentlylinked to an alkylene group, where heteroaryl and alkylene are definedherein.

“Optionally substituted heteroarylalkyl” refers to an optionallysubstituted heteroaryl group covalently linked to an optionallysubstituted alkylene group. Such heteroarylalkyl groups are exemplifiedby 3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, andthe like.

The term “heterocyclyl” refers to a saturated or partially unsaturatedgroup having a single ring or multiple condensed rings, having from 1 to40 carbon atoms and from 1 to 10 hetero atoms, preferably 1, 2, 3 or 4heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygenwithin the ring. Heterocyclic groups can have a single ring or multiplecondensed rings, and include tetrahydrofuranyl, morpholinyl,piperidinyl, piperazinyl, dihydropyridinyl, tetrahydroquinolinyl and thelike. Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents,selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo,—C(O)R where R is hydrogen, hydroxyl, alkoxy, alkyl and cycloalkyl,thiocarbonyl, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, and —S(O)_(p)R^(b),where R^(b) is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and pis 0, 1 or 2. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentsselected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)R^(c),where R^(c) is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “heterocyclylalkyl” refers to a heterocyclyl group covalentlylinked to an alkylene group, where heterocyclyl and alkylene are definedherein.

“Optionally substituted heterocyclylalkyl” refers to an optionallysubstituted heterocyclyl group covalently linked to an optionallysubstituted alkylene group.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “thiol” refers to the group —SH.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heteroarylthio” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O).

“Substituted sulfoxide” refers to a group —S(O)R, in which R issubstituted alkyl, substituted aryl, or substituted heteroaryl, asdefined herein.

The term “sulfone” refers to a group —S(O)₂R.

The term “substituted sulfone” refers to a group —S(O)₂R, in which R isalkyl, aryl, or heteroaryl.

The compounds of the present invention may have the ability tocrystallize in more than one form, a characteristic known aspolymorphism, and all such polymorphic forms (“polymorphs”) areencompassed within the scope of the invention. Polymorphism generallycan occur as a response to changes in temperature or pressure or both,and can also result from variations in the crystallization process.Polymorphs can be distinguished by various physical characteristics, andtypically the x-ray diffraction patterns, solubility behavior, andmelting point of the compound are used to distinguish polymorphs.

The compounds described herein may contain one or more chiral centersand/or double bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), regioisomers, enantiomersor diastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedor identified compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the person skilled in the art. The compoundsmay also exist in several tautomeric forms including the enol form, theketo form and mixtures thereof. Accordingly, the chemical structuresdepicted herein encompass all possible tautomeric forms of theillustrated or identified compounds.

Compounds may exist in unsolvated forms as well as solvated forms,including hydrated forms and as N-oxides. In general, compounds may behydrated, solvated or N-oxides. Certain compounds may exist in multiplecrystalline or amorphous forms. Also contemplated within the scope ofthe invention are congeners, analogs, hydrolysis products, metabolitesand precursor or prodrugs of the compound. In general, unless otherwiseindicated, all physical forms are equivalent for the uses contemplatedherein and are intended to be within the scope of the present invention.

“Prodrug” refers to a derivative of a drug molecule as, for example,esters, carbonates, carbamates, ureas, amides or phosphates thatrequires a transformation within the body to release the active drug.Prodrugs are frequently, although not necessarily, pharmacologicallyinactive until converted to the parent drug. Prodrugs may be obtained bybonding a promoiety (defined herein) typically via a functional group,to a drug.

“Promoiety” refers to a group bonded to a drug, typically to afunctional group of the drug, via bond(s) that are cleavable underspecified conditions of use. The bond(s) between the drug and promoietymay be cleaved by enzymatic or non-enzymatic means. Under the conditionsof use, for example following administration to a patient, the bond(s)between the drug and promoiety may be cleaved to release the parentdrug. The cleavage of the promoiety may proceed spontaneously, such asvia a hydrolysis reaction, or it may be catalyzed or induced by anotheragent, such as by an enzyme, by light, by acid, or by a change of orexposure to a physical or environmental parameter, such as a change oftemperature, pH, etc. The agent may be endogenous to the conditions ofuse, such as an enzyme present in the systemic circulation to which theprodrug is administered or the acidic conditions of the stomach or theagent may be supplied exogenously.

“Pharmaceutically acceptable salt” embraces salts with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids, for example hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid andorganic acids, for example citric, fumaric, maleic, malic, mandelic,ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic,ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.Pharmaceutically acceptable bases include alkali metal (e.g. sodium orpotassium) and alkali earth metal (e.g. calcium or magnesium) hydroxidesand organic bases, for example alkyl amines, arylalkyl amines andheterocyclic amines.

Other preferred salts according to the invention are quaternary ammoniumcompounds wherein an equivalent of an anion (X−) is associated with thepositive charge of the N atom. X− may be an anion of various mineralacids such as, for example, chloride, bromide, iodide, sulphate,nitrate, phosphate, or an anion of an organic acid such as, for example,acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate,malate, mandelate, trifluoroacetate, methanesulphonate andp-toluenesulphonate. X− is preferably an anion selected from chloride,bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinateor trifluoroacetate. More preferably X− is chloride, bromide,trifluoroacetate or methanesulphonate.

The present invention provides compounds of formula I, or its tautomers,polymorphs, stereoisomers, prodrugs, solvate or a pharmaceuticallyacceptable salts thereof, pharmaceutical compositions containing themand methods of treating conditions and diseases that are mediated byadenosine receptor activity.

In an embodiment of the present invention, it provides a compound offormula I

or its tautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein

-   -   Y is selected from N or CR; R is selected from H, hydroxy,        alkoxy, alkyl, or aryl;    -   R¹ is selected from a group consisting of alkyl, alkenyl and        alkynyl, wherein one or more methylene groups are optionally        replaced by hetero atoms or group selected from —O—, —S(O)p-,        —N(R^(a))—, or —C(O) provided that the heteroatom is not        adjacent to N in the ring; p is selected from 0, 1 or 2;        -   wherein alkyl, alkenyl and alkynyl are unsubstituted or            substituted independently with alkoxy, acyl, acylamino,            acyloxy, amino, mono alkylamino, dialkylamino,            aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,            haloalkyl, hydroxy, hydroxyalkyl, keto, thiocarbonyl,            carboxy, alkylcarboxy, carboxyalkyl, —SO₃H,            aminocarbonylamino, hydroxyamino, alkoxyamino, nitro,            —S(O)₂NR^(a)R^(a), —NR^(a)S(O)₂R^(a), or —S(O)_(p)R^(a);    -   R² is selected from a group consisting of hydrogen, halogen,        cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl,        alkynyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy,        alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b), cycloalkyl,        cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,        heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl,        heteroarylalkyl and heteroaryloxy;        -   wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl,            cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl,            aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            heteroaryl, heteroarylalkyl, heteroaryloxy and R^(b) are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro,            amino, mono alkylamino, dialkylamino, hydroxyamino,            alkoxyamino, aminocarbonylamino, azido, cyano, halogen,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, arylamino,            cycloalkylamino, heteroarylamino, heterocyclylamino,            aminocarbonyl, alkoxycarbonylamino, cycloalkyl,            cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl,            heteroaryloxy, heterocyclyl, heterocyclyloxy,            —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, haloalkyl, haloalkoxy, amino,                substituted amino, cyano or —S(O)_(p)R^(d);        -   R³ is selected from a group consisting of hydrogen, alkyl,            alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,            aryl, arylalkyl, heteroaryl and heteroarylalkyl;            -   wherein alkyl, alkenyl, alkynyl, alkoxyalkyl,                cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,                heteroaryl, and heteroarylalkyl are unsubstituted or                substituted independently with alkyl, alkenyl, alkynyl,                alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,                acyloxy, amino, monoalkylamino, dialkylamino, arylamino,                cycloalkylamino, heteroarylamino, heterocyclylamino,                aminocarbonyl, alkoxycarbonylamino, azido, cyano,                halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl,                carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,                alkylcarboxyalkyloxy, —SO₃H, aryl, aryloxy,                cycloalkyloxy, heteroaryl, aminocarbonylamino,                heteroaryloxy, heterocyclyl, heterocyclyloxy,                hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(c)R^(c),                —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);                -   wherein each substituent is unsubstituted or                    substituted with 1, 2, or 3 substituents                    independently selected from alkyl, carboxy,                    carboxyalkyl, aminocarbonyl, hydroxyd, alkoxy,                    halogen, haloalkyl, haloalkoxy, amino, substituted                    amino, cyano or —S(O)_(p)R^(d);    -   X is either an optionally substituted arylene or an optionally        substituted heteroarylene;    -   A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(p)—, —N(R^(b))—, or —C(O)—;        -   wherein alkylene, alkenylene, and alkynylene are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,            acylamino, acyloxy, amino, mono alkylamino, dialkylamino,            arylamino, cycloalkylamino, heteroarylamino,            heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,            azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,            thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl,            carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H, aryl, aryloxy,            cycloalkyloxy, heteroaryl, aminocarbonylamino,            heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino,            alkoxyamino, nitro, —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or            —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, CF₃, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or        heteroaryl;        -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,            cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,            aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl,            heteroarylalkyl, aminocarbonylamino, heteroaryloxy,            heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(b)R^(b),            —NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                haloalkoxy, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   R^(a) is independently selected from the group consisting of        hydrogen and alkyl;    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   R^(c) is selected from hydrogen, alkyl, aryl, heteroaryl or        heterocyclyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

According to another embodiment, the present disclosure relates tocompounds of formula (I) wherein,

-   -   Y is CR; R is selected from H, hydroxy, alkoxy, alkyl, or aryl;    -   R¹ is selected from a group consisting of alkyl, alkenyl and        alkynyl, wherein alkyl, alkenyl and alkynyl are unsubstituted or        substituted independently with alkoxy, acyl, acylamino, acyloxy,        amino, monoalkylamino, dialkylamino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxy,        hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, or        carboxyalkyl;    -   R² is selected from a group consisting of hydrogen, halogen,        cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl,        alkynyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, and        —NR^(b)R^(b);        -   wherein alkyl, alkenyl, alkynyl, alkoxy and R^(b) are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro,            amino, mono alkylamino, dialkylamino, hydroxyamino,            alkoxyamino, aminocarbonylamino, azido, cyano, halogen,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, arylamino,            cycloalkylamino, heteroarylamino, heterocyclylamino,            aminocarbonyl, alkoxycarbonylamino, cycloalkyl or            cycloalkenyl;    -   R³ is selected from a group consisting of hydrogen, alkyl,        alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,        heteroaryl and heteroarylalkyl;    -   X is either an optionally substituted arylene or an optionally        substituted heteroarylene;    -   A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(P), —N(R^(b))—, or —C(O)—;    -   B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or        heteroaryl;        -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,            cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,            aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl,            heteroarylalkyl, aminocarbonylamino, heteroaryloxy,            heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(b)R^(b),            —NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                haloalkoxy, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

According to an embodiment, the present disclosure relates to compoundsof formula (I) wherein, Y is N or CR; R is selected from H, hydroxy,alkoxy, alkyl, or aryl;

-   -   R¹ is selected from a group consisting of alkyl, alkenyl and        alkynyl;    -   R² is selected from a group consisting of hydrogen, halogen,        cyano, nitro, carboxy, acyl, alkyl, alkenyl, alkynyl, alkoxy,        —NR^(b)R^(b), cycloalkyl, cycloalkyoxy, aryl, aryloxy,        heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy;        -   wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,            cycloalkyoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy,            heteroaryl, heteroaryloxy and R^(b) are unsubstituted or            substituted independently with alkyl, alkenyl, alkynyl,            alkoxy, acyl, acylamino, acyloxy, nitro, amino,            monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino,            aminocarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, —SO₃H, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, cycloalkyl or cycloalkenyl;    -   R³ is selected from a group consisting of hydrogen, alkyl,        alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,        aryl, arylalkyl, heteroaryl and heteroarylalkyl;    -   X is an optionally substituted phenyl;    -   A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(p)—, —N(R^(b))—, or —C(O)—;    -   B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or        heteroaryl;        -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,            cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,            aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl,            heteroarylalkyl, aminocarbonylamino, heteroaryloxy,            heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(b)R^(b),            —NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                haloalkoxy, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

According to an embodiment, the present disclosure relates to compoundsof formula (I) wherein Y is selected from N or CR; R is selected from H,hydroxy, alkoxy, alkyl, or aryl;

-   -   R¹ is selected from a group consisting of alkyl, alkenyl and        alkynyl;        -   wherein alkyl, alkenyl and alkynyl are unsubstituted or            substituted independently with alkoxy, acyl, acylamino,            acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, haloalkyl,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, aminocarbonylamino,            hydroxyamino, alkoxyamino or nitro;    -   R² is selected from a group consisting of hydrogen, halogen,        cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl,        alkynyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy,        alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b), cycloalkyl,        cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,        heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy;        -   wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl,            cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl,            aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and            heteroaryloxy and R^(b) are unsubstituted or substituted            independently with alkyl, alkenyl, alkynyl, alkoxy, acyl,            acylamino, acyloxy, nitro, amino, mono alkylamino,            dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino,            azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,            thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO₃H,            arylamino, cycloalkylamino, heteroarylamino,            heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,            cycloalkyl, cycloalkyloxy, aryl, aryloxy, heterocyclyl,            heterocyclyloxy, heteroaryl, heteroaryloxy,            —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, haloalkyl, haloalkoxy, amino,                substituted amino, cyano or —S(O)_(p)R^(d);    -   R³ is selected from a group consisting of hydrogen, alkyl,        alkenyl and alkynyl;        -   wherein alkyl, alkenyl and alkynyl are unsubstituted or            substituted independently with alkyl, alkenyl, alkynyl,            alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SO₃H,            aryl, aryloxy, cycloalkyloxy, heteroaryl,            aminocarbonylamino, heteroaryloxy, heterocyclyl,            heterocyclyloxy, hydroxyamino, alkoxyamino or nitro;    -   X is an optionally substituted heteroarylene;    -   A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(p)—, —N(R^(b))—, or —C(O)—;        -   wherein alkylene, alkenylene, and alkynylene are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino,            acyloxy, amino, mono alkylamino, dialkylamino, arylamino,            cycloalkylamino, heteroarylamino, heterocyclylamino,            aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, carboxyalkyloxy,            alkylcarboxyalkyloxy —SO₃H, aryl, aryloxy, cycloalkyloxy,            heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl,            heterocyclyloxy, hydroxyamino, alkoxyamino or nitro;    -   B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or        heteroaryl;        -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,            cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,            aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl,            heteroarylalkyl, aminocarbonylamino, heteroaryloxy,            heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(b)R^(b),            —NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                haloalkoxy, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   Rc is selected from hydrogen, alkyl, aryl, heteroaryl or        heterocyclyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

According to another embodiment, the present disclosure relates tocompounds of formula (I) wherein X is selected from

According to an embodiment, the present disclosure relates to compoundsof formula (I) wherein B is selected from

According to an embodiment, the present disclosure relates to compoundsof formula (I) wherein A is selected from

According to an embodiment, the present disclosure relates to compoundsof formula (I) wherein Y is selected from N or CR; R is selected from H,hydroxy, alkoxy, alkyl, or aryl;

-   -   R¹ is alkyl wherein alkyl is unsubstituted or substituted        independently with alkoxy, acyl, acylamino, acyloxy, cyano,        halogen, hydroxy, carboxy, carboxyalkyl or nitro;    -   R² is selected from a group consisting of hydrogen, halogen,        cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, hydroxyalkyl,        carboxyalkyl, alkoxy, —NR^(b)R^(b), cycloalkyl, aryl, arylalkyl,        aryloxy, heterocyclyl and heteroaryl;        -   wherein alkyl, alkoxy, cycloalkyl, aryl, arylalkyl,            heteroaryl, heterocyclyl and R^(b) are unsubstituted or            substituted independently with alkyl, alkoxy, acyl, acyloxy,            nitro, amino, hydroxyamino, alkoxyamino, aminocarbonylamino,            cyano, halogen, hydroxy, hydroxyalkyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, aminocarbonyl,            cycloalkyl, cycloalkyloxy, aryl, aryloxy, heterocyclyl,            heterocyclyloxy, heteroaryl or heteroaryloxy;    -   R³ is selected from a group consisting of hydrogen, alkyl, aryl        and arylalkyl;        -   wherein alkyl, aryl and arylalkyl are unsubstituted or            substituted independently with alkyl, acyl, acylamino,            acyloxy, amino, cyano, halogen, hydroxy, carboxy,            alkylcarboxy or carboxyalkyl;    -   X is either an optionally substituted arylene or an optionally        substituted heteroarylene;    -   A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(P), —N(R^(b))—, or —C(O)—;    -   B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or        heteroaryl;        -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,            cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,            aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl,            heteroarylalkyl, aminocarbonylamino, heteroaryloxy,            heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(b)R^(b),            —NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                haloalkoxy, amino, substituted amino, cyano or                —S(O)_(p)R^(c);    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   R^(c) is selected from hydrogen, alkyl, aryl, heteroaryl or        heterocyclyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

According to an embodiment, the present disclosure relates to compoundsof formula (I) wherein Y is N;

-   -   R¹ is an alkyl, wherein one or more methylene groups are        replaced by hetero atoms or groups such as —O—, —S(O)p-,        —N(R^(a))—, or —C(O) provided that the heteroatom is not        adjacent to N in the ring; p is selected from 0, 1 or 2;        -   wherein alkyl is unsubstituted or substituted independently            with alkoxy, acyl, acylamino, acyloxy, amino, mono            alkylamino, dialkylamino, aminocarbonyl,            alkoxycarbonylamino, cyano, halogen, haloalkyl, hydroxy,            hydroxyalkyl, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, —SO₃H, aminocarbonylamino, hydroxyamino,            alkoxyamino, —S(O)₂NR^(a)R^(a), —NR^(a)S(O)₂R^(a), or            —S(O)_(p)R^(a);    -   R² is selected from a group consisting of hydrogen, halogen,        cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl,        alkynyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy,        alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b), cycloalkyl,        cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,        heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl,        heteroarylalkyl and heteroaryloxy;        -   wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl,            cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl,            aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            heteroaryl, heteroarylalkyl, heteroaryloxy and R^(b) are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro,            amino, mono alkylamino, dialkylamino, hydroxyamino,            alkoxyamino, aminocarbonylamino, azido, cyano, halogen,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, arylamino,            cycloalkylamino, heteroarylamino, heterocyclylamino,            aminocarbonyl, alkoxycarbonylamino, cycloalkyl,            cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl,            heteroaryloxy, heterocyclyl, heterocyclyloxy,            —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, haloalkyl, haloalkoxy, amino,                substituted amino, cyano or —S(O)_(p)R^(d);    -   R³ is selected from a group consisting of hydrogen, alkyl and        arylalkyl;    -   X is an optionally substituted heteroarylene;    -   A is selected from (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(p)—, —N(R^(b))—, or —C(O)—;        -   wherein alkylene, alkenylene, and alkynylene are            unsubstituted or substituted independently with alkyl,            alkoxy, cycloalkyl, halogen, hydroxy, hydroxyalkyl, carboxy,            alkylcarboxy, carboxyalkyl, carboxyalkyloxy, —SO₃H,            hydroxyamino, alkoxyamino, S(O)₂NR^(c)R^(c),            —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);        -   B is selected from heterocyclyl, cycloalkyl, aryl or            heteroaryl;            -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl                are unsubstituted or substituted independently with                alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,                cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy,                amino, mono alkylamino, dialkylamino, arylamino,                cycloalkylamino, heteroarylamino, heterocyclylamino,                aminocarbonyl, alkoxycarbonylamino, azido, cyano,                halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl,                carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,                alkylcarboxyalkyloxy —SO₃H, aryl, arylalkyl, aryloxy,                cycloalkyloxy, heteroaryl, heteroarylalkyl,                aminocarbonylamino, heteroaryloxy, heterocyclyl,                heterocyclylalkyl, heterocyclyloxy, hydroxyamino,                alkoxyamino, nitro, —S(O)₂NR^(b)R^(b), —NR^(b)S(O)₂R^(b)                or —S(O)_(p)R^(d);                -   wherein each substituent is unsubstituted or                    substituted with 1, 2, or 3 substituents                    independently selected from alkyl, carboxy,                    carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,                    alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                    haloalkoxy, amino, substituted amino, cyano and                    —S(O)_(p)R^(d);    -   R^(a) is independently selected from the group consisting of        hydrogen and alkyl;    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   R^(c) is selected from hydrogen, alkyl, aryl, heteroaryl or        heterocyclyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

A specific embodiment of the compounds of formula (I) is selected from:

-   8-(4-Benzyloxy-phenyl)-1-propyl-1,7-dihydro-purin-6-one,-   1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   8-[1-(2,3-Difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   1-Propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   1-Propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one,-   2-Chloro-8-[1-(3-fluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   8-[1-(2,4-Difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one,-   8-{-4-[5-oxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-ylmethoxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one,-   1-Propyl-8-{4-[3-(3-trifluoromethyl-phenyl)-prop-2-ynyloxy]phenyl}-1,7-dihydro-purin-6-one,-   8-{-4-[5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethoxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-8-[1-(2,4-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   8-[1-(3-Fluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Morpholin-4-yl-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   N-(4-Cyano-phenyl)-2-[4-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetamide,-   [4-(6-Oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetic acid,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one,-   8-(4-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-phenyl)-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-(3-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-[2-(4-methoxy-phenyl)-ethylamino]-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-phenethylamino-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-(4-methyl-piperazin-1-yl)-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-piperidin-1-yl-1-propyl-1,7-dihydro-purin-6-one,-   8-{1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one,-   8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(2-hydroxy-ethylamino)-1-propyl-1,7-dihydro-purin-6-one,-   2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one,-   [8-(1-Benzyl-1H-pyrazol-4-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-ylamino]-acetic    acid ethyl ester,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one,-   1,2-Dipropyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,-   1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,-   2-(3-Fluoro-phenyl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Dimethylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carbonitrile,-   8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carboxylic    acid,-   8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,-   8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,-   8-(4-Methoxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,-   2-Ethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Benzyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   {6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-acetic    acid,-   (S)-1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic    acid,-   1-Propyl-2-pyrrolidin-1-yl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Methylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Cyclobutylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-7-methyl-1-propyl-1,7-dihydro-purin-6-one,

2-Methoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,

-   6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile,-   2-Cyclopentyloxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylic    acid amide,-   {6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-acetic    acid ethyl ester,-   2-Morpholin-4-yl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1,1-purin-2-yloxy}-acetic    acid,-   8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one,-   (S)-1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic    acid amide,-   1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-piperidine-3-carboxylic    acid,-   1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1,1-purin-2-yl}-piperidine-4-carboxylic    acid,-   (2R,4R)-4-Hydroxy-1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic    acid,-   2-(2,3-Dihydroxy-propylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-(2-Methoxy-ethylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-(4-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-(3-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-ethanesulfonic    acid,-   2-(3-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   (Methyl-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-amino)-acetic    acid,-   2-(2-Hydroxy-ethylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-(4-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-(4-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   (S)-3-Methyl-2-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-butyric    acid,-   2-((S)-2-Methoxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-((R)-3-Hydroxy-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   1-Propyl-2-(tetrahydro-pyran-4-ylamino)-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Fluoro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   1-Propyl-2-(2,2,2-trifluoro-ethoxy)-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-(2-Methoxy-ethoxy)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   7-Methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Chloro-1-propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one,-   2-Chloro-8-[6-(3-fluoro-benzylamino)-pyridin-3-yl]-1-propyl-1,7-dihydro-purin-6-one,-   1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one,-   1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one,-   1-Propyl-8-[1-(6-trifluoromethyl-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Cyclopropyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   1-Propyl-2-trifluoromethyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-Isobutylamino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one,-   2-[2-(4-Methoxy-phenyl)-ethylamino]-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-(4-Methyl-piperazin-1-yl)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   1-[8-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-yl]-pyrrolidine-2-carboxylic    acid methyl ester,-   2-Benzyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-(3-Fluoro-phenyl)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,-   8-(1-Methyl-1H-pyrazol-4-yl)-2-phenethylamino-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,-   2-Cyclopropylamino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-(3-Fluoro-phenoxy)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-(4-Methoxy-phenylamino)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   7-Benzyl-2-chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   9-Benzyl-2-chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,9-dihydro-purin-6-one,-   2-Amino-7-benzyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-8-furan-2-yl-1-propyl-1,7-dihydro-purin-6-one,-   2-Amino-8-[1-(4-fluoro-benzyl)-1H-imidazo[1,2-b]pyrazol-7-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-8-[1-(4-fluoro-benzyl)-1H-imidazo[1,2-b]pyrazol-7-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Amino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-Amino-7-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-Amino-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,9-dihydro-purin-6-one,-   7-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   9-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,9-dihydro-purin-6-one,-   2-Amino-8-furan-2-yl-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-8-furan-2-yl-7-methyl-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-(3-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,-   2-Furan-2-yl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,-   8-(1-Benzyl-1H-pyrazol-4-yl)-2-furan-2-yl-1-propyl-1,7-dihydro-purin-6-one,-   2-Chloro-8-(6-chloro-pyridin-3-yl)-1-propyl-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Fluoromethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Fluoromethyl-8-{1-[3-(3-methoxy-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-8-{1-[2-oxo-2-(4-m-tolyl-piperazin-1-yl)-ethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one,-   3-Fluoro-N-methyl-N-[5-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-benzamide,-   N-[5-(2-Difluoromethyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-N-methyl-benzamide,-   N-[5-(2-Difluoromethyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,-   2-Fluoromethyl-1-propyl-8-[1-(5-trifluoromethyl-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Fluoromethyl-1-propyl-8-[1-(2-trifluoromethyl-pyridin-4-ylmethyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Fluoromethyl-8-[3-(3-methoxy-phenoxy)-isoxazol-5-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-8-{3-[3-(3-fluoro-phenyl)-prop-2-ynyloxy]-isoxazol-5-yl}-1-propyl-1,7-dihydro-purin-6-one,-   2-Fluoromethyl-1-(2-hydroxy-ethyl)-8-[3-(3-methoxy-phenoxy)-isoxazol-5-yl]-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-1-ethyl-8-{3-[3-(3-fluoro-phenyl)-prop-2-ynyloxy]-isoxazol-5-yl}-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-1-ethyl-8-(1-{2-[4-(3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one,-   1-Ethyl-8-(1-{2-[4-(3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile,-   N-[5-(2-Cyano-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,-   N-{5-[2-Cyano-1-(2-hydroxy-ethyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]-pyridin-2-yl}-3-methoxy-benzenesulfonamide,-   2-Difluoromethyl-1-ethyl-8-{4-[3-(3-methoxy-phenyl)-prop-2-ynyloxy]-phenyl}-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-1-ethyl-8-{4-[1-(3-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-phenyl}-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-8-[5-(3-methoxy-phenoxy)-1-methyl-1H-pyrazol-3-yl]-1-propyl-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-8-{5-[1-(3-methoxy-phenyl)-piperidin-4-yloxy]-1-methyl-1H-pyrazol-3-yl}-1-propyl-1,7-dihydro-purin-6-one,-   2-Fluoromethyl-8-{3-[1-(3-fluoro-phenyl)-piperidin-4-yloxy]-isoxazol-5-yl}-1-propyl-1,7-dihydro-purin-6-one,-   1-Ethyl-8-{6-[1-(3-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-pyridin-3-yl}-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile,-   1-Ethyl-8-{6-[1-(3-methoxy-phenyl)-pyrrolidin-3-yloxy]-pyridin-3-yl}-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile,-   3-[4-(2-Difluoromethyl-1-ethyl-6-oxo-6,7-dihydro-1H-purin-8-yl)-pyrazol-1-ylmethyl]-benzoic    acid,-   2-Difluoromethyl-1-ethyl-8-[1-(3-hydroxymethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   2-Difluoromethyl-3-ethyl-6-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,-   N-[5-(2-Cyano-4-oxo-3-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,-   2-Fluoromethyl-6-{3-[1-(3-fluoro-phenyl)-piperidin-4-yloxy]-isoxazol-5-yl}-3-propyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,-   2-Difluoromethyl-6-{5-[1-(3-methoxy-phenyl)-piperidin-4-yloxy]-1-methyl-1H-pyrazol-3-yl}-3-propyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,-   3-Ethyl-6-{6-[1-(3-methoxy-phenyl)-pyrrolidin-3-yloxy]-pyridin-3-yl}-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-carbonitrile,-   2-Fluoromethyl-6-{3-[1-(3-fluoro-phenyl)-piperidin-4-yloxy]isoxazol-5-yl}-7-hydroxy-3-propyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,-   2-Difluoromethyl-3-ethyl-6-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-7-methyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,-   2-Difluoromethyl-1-ethyl-8-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-7-methyl-1,7-dihydro-purin-6-one,-   N-[5-(2-Cyano-7-methyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,-   1-(2,2-Difluoro-ethyl)-2-ethyl-8-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,-   3-{3-[4-(2-Difluoromethyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzoic    acid,-   3-(3-{4-[1-(2,2-Difluoro-ethyl)-2-ethyl-6-oxo-6,7-dihydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzoic    acid,-   3-{3-[4-(6-oxo-1-propyl-2-trifluoromethyl-6,7-dihydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzoic    acid, or-   6-oxo-1-propyl-8-[6-(3-trifluoromethyl-benzyl)-pyridin-3-yl]-6,7-dihydro-1H-purine-2-carbonitrile.

In still another embodiment of the present invention, the compound offormula I forms a pharmaceutically acceptable salt, selected from acidaddition salts or base addition salts.

In still another embodiment of the present invention, the compound offormula I is a stereoisomer or a tautomer.

It is another feature of the present invention to provide the use ofcompounds of formula (II) or its tautomers, polymorphs, stereoisomers,prodrugs, solvate or a pharmaceutically acceptable salts thereof, forthe treatment of a pathological disease susceptible to improvement byantagonism of adenosine receptors,

wherein Y is selected from N and CR; R is selected from H, hydroxy,alkoxy, alkyl, aryl;

-   -   R¹ is selected from a group consisting of alkyl, alkenyl,        alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;        wherein one or more methylene groups of alkyl, alkenyl, alkynyl,        are replaced by hetero atoms or groups such as —O—, —S(O)p-,        NR^(a)R^(a), or —C(O)—, provided that the heteroatom is not        adjacent to N in the ring; p is selected from 0, 1 or 2;        -   wherein alkyl, alkenyl, alkynyl, cycloalkyl,            cycloalkylalkyl, aryl, arylalkyl, heterocyclyl,            heterocyclylalkyl, heteroaryl and heteroarylalkyl are            unsubstituted or substituted with alkyl, alkenyl, alkynyl,            alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,            amino, monoalkylamino, dialkylamino, arylamino,            cycloalkylamino, heteroarylamino, heterocyclylamino,            aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, aryl, aryloxy,            cycloalkyloxy, heteroaryl, aminocarbonylamino,            heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino,            alkoxyamino, nitro, —S(O)₂NR^(a)R^(a), —NR^(a)S(O)₂R^(a),            —S(O)_(p)R^(b), cycloalkyl, aryl, heterocyclyl or            heteroaryl;            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, haloalkyl, haloalkoxy, amino,                substituted amino, cyano or —S(O)_(p)R^(c);    -   R² is selected from a group consisting of hydrogen, halogen,        cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl,        alkynyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy,        alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b), cycloalkyl,        cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,        heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl,        heteroarylalkyl and heteroaryloxy;        -   wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl,            cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl,            aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            heteroaryl, heteroarylalkyl, heteroaryloxy and R^(b) are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro,            amino, mono alkylamino, dialkylamino, hydroxyamino,            alkoxyamino, aminocarbonylamino, azido, cyano, halogen,            hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy,            alkylcarboxy, carboxyalkyl, —SO₃H, arylamino,            cycloalkylamino, heteroarylamino, heterocyclylamino,            aminocarbonyl, alkoxycarbonylamino, cycloalkyl,            cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl,            heteroaryloxy, heterocyclyl, heterocyclyloxy,            —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, haloalkyl, haloalkoxy, amino,                substituted amino, cyano or —S(O)_(p)R^(d);    -   R3 is selected from a group consisting of hydrogen, alkyl,        alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,        aryl, arylalkyl, heteroaryl and heteroarylalkyl;        -   wherein alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl,            cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and            heteroarylalkyl are unsubstituted or substituted            independently with alkyl, alkenyl, alkynyl, alkoxy,            cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,            mono alkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SO₃H,            aryl, aryloxy, cycloalkyloxy, heteroaryl,            aminocarbonylamino, heteroaryloxy, heterocyclyl,            heterocyclyloxy, hydroxyamino, alkoxyamino, nitro,            S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyd,                alkoxy, halogen, CF₃, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   X is either an optionally substituted arylene or an optionally        substituted heteroarylene;    -   A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or        (C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are        optionally replaced by groups independently selected from O,        —S(O)_(p)—, —N(R^(b))—, or —C(O)—;        -   wherein alkylene, alkenylene, and alkynylene are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,            acylamino, acyloxy, amino, mono alkylamino, dialkylamino,            arylamino, cycloalkylamino, heteroarylamino,            heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,            azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,            thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl,            carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H, aryl, aryloxy,            cycloalkyloxy, heteroaryl, aminocarbonylamino,            heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino,            alkoxyamino, nitro, S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or            —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, halogen, CF₃, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or        heteroaryl;        -   wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are            unsubstituted or substituted independently with alkyl,            alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,            cycloalkenyl, acyl, acylamino, acyloxy, amino,            monoalkylamino, dialkylamino, arylamino, cycloalkylamino,            heteroarylamino, heterocyclylamino, aminocarbonyl,            alkoxycarbonylamino, azido, cyano, halogen, hydroxy,            hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,            carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,            aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl,            heteroarylalkyl, aminocarbonylamino, heteroaryloxy,            heterocyclyl, heterocyclylalkyl, heterocyclyloxy,            hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(b)R^(b),            —NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d);            -   wherein each substituent is unsubstituted or substituted                with 1, 2, or 3 substituents independently selected from                alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,                alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl,                haloalkoxy, amino, substituted amino, cyano or                —S(O)_(p)R^(d);    -   R^(a) is independently selected from the group consisting of        hydrogen and alkyl;    -   R^(b) is independently selected from the group consisting of        hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl,        heterocyclyl and heterocyclylalkyl;    -   R^(c) is selected from hydrogen, alkyl, aryl, heteroaryl or        heterocyclyl;    -   R^(d) is selected from alkyl, cycloalkyl, aryl, heterocyclyl or        heteroaryl;    -   and p is 0, 1 or 2.

The present invention also relates to the process of preparation ofcompounds of formula (I), or pharmaceutically acceptable salts thereof.

The compounds of formula (I) may be prepared as outlined in Scheme 1 and2 below:

As exemplified in Scheme 1 above, diamine of formula (III) where in R¹is as defined herein above, may be coupled with carboxylic acid offormula (IV) or its acid chloride wherein all symbols are defined hereinabove and cyclised to provide compounds of formula (V) which may bechlorinated followed by reacting with R²-LG wherein LG is NH₂, B(OH)₂,MgBr, ZnCl, OH and R² is defined herein above to provide compounds offormula (I) wherein R³ is hydrogen and all other symbols are definedherein above. Compounds of formula (I) may further be reacted withR³-Hal to provide compounds of formula (I) wherein R³ is other thanhydrogen and is as defined herein above.

As exemplified in Scheme 2 above, diamine of formula (III) where in R¹is as defined herein above, may be coupled with carboxylic acid offormula (VI) or its acid chloride wherein PG is a protecting group andall other symbols are defined herein above and cyclised to providecompounds of formula (VII) which may be chlorinated followed by reactingwith R²-LG wherein LG is NH₂, B(OH)₂, MgBr, ZnCl, OH and R² is definedherein above followed by protection of the amino group to providecompounds of formula (VIII) which may be reacted with compounds offormula (IX) wherein L1 is a leaving group and A and B are as definedherein above followed by deprotection to provide compounds of formula(I) wherein R³ is hydrogen and all other symbols are defined hereinabove. Compounds of formula (I) may further be reacted with R³-Hal toprovide compounds of formula (I) wherein R³ is other than hydrogen andis as defined herein above.

Schemes 3-7 further describes synthesis of compounds of formula (I)

As exemplified in scheme 3 above, pyrimidine derivative of formula (1a)which is available commercially may be reacted with PG-NH₂ such asbenzylamine, allylamine and the like to obtain compound of formula (1b).The reaction may be carried out in a solvent such as ethanol, methanol,THF and the like, in an inert atmosphere. The reaction temperature mayrange from 40° C. to 70° C. The reaction time may range from 6 to 20hours.

The compound of formula (1b) may be condensed with an aldehyde offormula (1c) in the presence of a suitable solvent or a mixture ofsolvents, preferably mixture of acetic acid and THF, then refluxed withformic acid to obtain the compound of formula (1d) wherein PG is aprotective group and all other symbols are as defined herein above. Thereaction temperature may range from 80° C. to 120° C. The reaction timemay range from 12 to 36 hours.

The compounds of formula (1d) may be converted into compounds of formula(1e) by reacting with R¹-Hal wherein R¹ is defined herein above. Thereaction may be carried out in a solvent such as acetone or DMF, in thepresence of a base such as K₂CO₃, Cs₂CO₃ or in presence of a suitableorganic base such as DBU. The reaction temperature may range from 20 to40° C.

The protecting group of the compound of (1e) may be removed by meanswell known in the art to provide compounds of formula I, wherein R³ isH, which is reacted with R³-Hal wherein R³ is defined herein above toprovide the desired compound of formula (I) wherein R³ is not H and allother symbols are as defined herein above.

The compounds of formula (1d) may also be prepared by reacting acidchloride of formula (2a) with (1b) to provide (2b). The reaction may becarried out in a basic solvent such as pyridine, N-methylpyrrolidinoneand the like or alternatively in an inert solvent such as THF, DCM,N,N-dimethyl acetamide and the like in presence of suitable organic basesuch as triethylamine, diisopropyl amine and the like. The reactiontemperature may range from 0° C. to room temperature. The reaction timemay range from 4 to 48 hours. The acid halides (2a) may be commerciallyavailable or can be prepared by conventional methods well-known to thoseskilled in the art. The intermediate (2b) may then be cyclized to obtaincompounds of formula (Id) by refluxing in a weak acid such as formicacid, acetic acid and the like or with sulphuric acid in an appropriatesolvent such as isopropanol, toluene and the like. The reaction time mayrange from 6-36 hours.

The compounds of formula (1d) may be converted into compounds of formula(1e) by reaction with R¹-Hal wherein R¹ is defined herein above. Thereaction may be carried out in a solvent such as acetone or DMF, in thepresence of a base such as K₂CO₃, Cs₂CO₃ or in presence of a suitableorganic base such as DBU. The reaction temperature may range from 20 to40° C.

The protecting group of the compound of (1e) may be removed by meanswell known in the art to provide compounds of formula I, wherein R³ isH, which is reacted with R³-Hal wherein R³ is defined herein above toprovide the desired compound of formula (I) wherein R³ is not H and allother symbols are as defined herein above.

The compound of formula (3a), wherein all symbols are defined earlier isprepared by means well known in the art (US2008/0194593).

A compound of formula (3a) is reacted with a carboxylic acid of formula(3b), (which is available commercially or prepared by means well knownin the art), wherein all symbols are defined earlier, to yield acompound of formula (3c). The reaction may be carried out using asuitable coupling agent such as EDCI, DCC, HBTU, HATU and the like in aprotic solvent such as methanol, ethanol, propanol and the like or anaprotic solvent such as DMF, CH₂Cl₂ and the like at a temperature in therange of 20-30° C. for 4 to 16 hours to provide compound of formula(3c).

The compound (3c) may also be prepared from reaction of (3a) with anacid halide of (3b). The reaction is carried out in a solvent such asacetonitrile, THF and the like, in the presence of tertiary base such astriethyl amine. The reaction temperature may range from 0° C. to refluxtemperature of the solvent(s) used. The reaction time may range from 4to 48 hours. After completion of reaction the product of formula (3c) isisolated by conventional methods.

The compound of formula (3c) is cyclised to obtain compounds of formula(3d) by a cyclization reaction. The reaction may be carried out in thepresence of hexamethyldisilazane and ammonium sulphate for about 24-48hours at reflux temperature.

Compounds of formula (3d) may be converted to compounds of formula (3e)by treatment with dehydrating agent such as POCl₃ or in combination withPOCl₃ and PCl₅, at reflux temperature for about 24 hours. Alternatively(3c) may be converted into compounds of formula (3e) by reaction withdehydrating agent such as POCl₃ or in combination with POCl₃—PCl₅, atreflux temperature for about 24 hours.

Dehalogenation of the compounds of formula (3e) may be carried out usinghydrogenation or by transfer hydrogenation in the presence of a suitablecatalyst such as Pd/C, Pd(OH)₂/C and the like. In general, the compoundof formula (3e) may be dissolved in DMF and treated with ammoniumformate in presence of 10% Pd/C and water at a temperature of about60-65° C. The reaction time may range from 1 to 18 hours. Aftercompletion of reaction, the compounds of formula (I) wherein R² and R³are hydrogen and all other symbols are defined herein above may beisolated by conventional methods.

Alternatively, compounds of formula (3e) may be converted to compoundsof formula (I) by reacting with R²—NH₂, R²R²NH, R²—B(OH)₂, R²MgBr,R²ZnCl, R²OH wherein R² is defined herein above, by methods well knownin the art to provide compounds of formula I, wherein R³ is H and allother symbols are defined herein above which may be further reacted withR³-Hal wherein R³ is defined herein above to provide the desiredcompound of formula (I) wherein R³ is not H and all other symbols are asdefined herein above.

The compound of formula (4a) wherein all symbols are defined earlier isprepared by means well known in the art (J. Med. Chem., 2005, 48,2420-2431, J. Org. Chem., 2000, 65, 2603-2605). The compound of formula(4a) can be converted to compound (4c) by reaction with appropriateisocyanate of formula (4b), wherein all symbols are defined earlier. Thereaction may be carried out in an inert solvent, for example toluene,benzene and the like. The reaction temperature may range from roomtemperature to reflux temperature of the solvent used, preferably atroom temperature. The reaction time may range from 1 to 24 hours. Aftercompletion of reaction, the product of formula (4c) is isolated byconventional method.

The compound of formula (4c) is then converted into a compound ofgeneral formula (4d) by a cyclization reaction. The reaction may becarried out in a protic solvent, for example methanol, ethanol, propanoland the like, preferably methanol, in presence of a base, for examplealkali metal hydroxide such as potassium hydroxide, sodium hydroxide andthe like, or sodium methoxide, sodium ethoxide, potassium tert-butoxide,preferably aqueous potassium hydroxide, at a temperature 50-100° C.,preferably at 80° C. The reaction time may range from 1 to 12 hours,preferably about 6-10 hours. After completion of reaction the product offormula (4d) is isolated by conventional method.

Compounds of formula (4d) may be converted to compounds of formula (4e)by treatment with dehydrating agent POCl₃ or in combination withPOCl₃—PCl₅, at reflux temperature for about 24 hours. After completionof reaction, (4e) is isolated conventionally.

Dehalogenation of the compounds of formula (4e) may be carried out usinghydrogenation or by transfer hydrogenation in the presence of a suitablecatalyst such as Pd/C, Pd(OH)₂/C and the like. In general, the compoundof formula (4e) may be dissolved in DMF and treated with ammoniumformate in presence of 10% Pd/C and water at a temperature of about60-65° C. The reaction time may range from 1 to 18 hours. Aftercompletion of reaction, the compounds of formula (I) wherein R² and R³are hydrogen and all other symbols are defined herein above may beisolated by conventional methods.

Alternatively, compounds of formula (4e) may be converted to compoundsof formula (I) by reacting with R²—NH₂, R²R²NH, R²—B(OH)₂, R²MgBr,R²ZnCl, R²OH wherein R² is defined herein above, by methods well knownin the art to provide compounds of formula I, wherein R³ is H and allother symbols are defined herein above which may be further reacted withR³-Hal wherein R³ is defined herein above to provide the desiredcompound of formula (I) wherein R³ is not H and all other symbols are asdefined herein above.

The compound of formula (5a) wherein all symbols are as defined earlieris prepared by means well known in the art. The compound of formula (5b)wherein all the symbols are defined as earlier is prepared by methods asdescribed in Scheme 3. The compound of formula (5c), wherein all thesymbols are as defined earlier and PG is the protecting group such asbenzyl and the like, may be prepared from compound of formula (5b) byreaction with PG1-Hal wherein PG1 may be SEM, and the like. The reactionmay be carried out using base such as K₂CO₃ and aprotic solvent forexample DMF, DMSO, acetonitrile and the like. The reaction temperaturemay range from room temperature to reflux temperature of the solventused, preferably at room temperature. The reaction time may range from 1to 24 hours. After completion of reaction, the product of formula (5c)is isolated by conventional method.

The compounds of formula (5c) may be converted to compounds of formula(5d) by reacting with R²—NH₂, R²R²NH, R²—B(OH)₂, R²MgBr, R²ZnCl, R²OHwherein R² is defined herein above, by methods well known in the art toprovide compounds of formula (5d).

The compounds of formula (5d) may be converted to compounds of formula(I) by deprotection of PG and followed by reaction with L1-A-B whereinA, B are defined herein above and L1 is leaving group such as halo(chloro, bromo, iodo etc), mesylate, tosylate and the like. The reactionmay be carried out in a solvent such as acetone or DMF, in the presenceof a base such as K₂CO₃, Cs₂CO₃ and the like. The reaction temperaturemay range from room temperature to reflux temperature of the solventused, preferably at 50-80° C. The reaction time may range from 1 to 24hours. The deprotection of PG1 can be carried out either using acidiccondition or basic condition depending on the nature of PG1. Aftercompletion of reaction, the product of formula (I) is isolated byconventional method, wherein R³ is H and all other symbols are definedherein above which may be further reacted with R³-Hal wherein R³ isdefined herein above to provide the desired compound of formula (I)wherein R³ is not H and all other symbols are as defined herein above.

Wherever desired or necessary, in any of the above mentioned processes,functional groups may be transformed to different functional groups suchas an ester function being converted to an acid, amide, hydroxymethyl,keto, aldehyde as well as an ester. The said conversions may be carriedout using reagents and conditions well documented in the literature.

Wherever desired or necessary, in any of the above mentioned processes,any of the compounds of formula (I) may be converted into apharmaceutically acceptable salt or vice versa or converting one saltform into another pharmaceutically acceptable salt form. According to anembodiment, the compounds of the present invention are adenosine A_(2B)receptor antagonists. Thus, the present invention provides a method forthe modulation of adenosine A_(2B) receptor activity in mammals whichmethod comprises administering to a mammal in need thereof atherapeutically effective amount of compound of formula I or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof.

According to another embodiment, it provides the use of compounds offormula II as adenosine A_(2B) receptor antagonists. Thus, the presentinvention provides a method for the modulation of adenosine A_(2B)receptor activity in mammals which method comprises administering to amammal in need thereof a therapeutically effective amount of compound offormula II or its tautomers, polymorphs, stereoisomers, prodrugs,solvate or a pharmaceutically acceptable salts thereof.

According to an embodiment, the compounds of the present invention areadenosine A_(2A) receptor antagonists. Thus, the present inventionprovides a method for the modulation of adenosine A_(2A) receptoractivity in mammals which method comprises administering to a mammal inneed thereof a therapeutically effective amount of compound of formula Ior its tautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof.

According to yet another embodiment, it provides the use of compound offormula II as adenosine A_(2A) receptor antagonists. Thus, the presentinvention provides a method for the modulation of adenosine A_(2A)receptor activity in mammals which method comprises administering to amammal in need thereof a therapeutically effective amount of compound offormula II or its tautomers, polymorphs, stereoisomers, prodrugs,solvate or a pharmaceutically acceptable salts thereof.

According to yet another embodiment, the compounds of the presentinvention are adenosine A_(2A) and A_(2B) antagonist or adenosine A₁ andA_(2B) antagonist or A₁, A_(2A) and A_(2B) antagonist thereby providingdual or pan antagonistic activity through additive/synergistic effect.Thus, the present invention provides a method for the modulation ofadenosine A_(2A) and A_(2B) or A₁ and A_(2B) or A₁, A_(2A) and A_(2B)receptor activity in mammals which method comprises administering to amammal in need thereof a therapeutically effective amount of compound offormula I or its tautomers, polymorphs, stereoisomers, prodrugs, solvateor a pharmaceutically acceptable salts thereof.

Yet in another embodiment it provides the use of compounds of formula IIas adenosine A_(2A) and A_(2B) antagonist or adenosine A₁ and A_(2B)antagonist or A₁, A_(2A) and A_(2B) antagonist thereby providing dual orpan antagonistic activity through additive/synergistic effect. Thus, thepresent invention provides a method for the modulation of adenosineA_(2A) and A_(2B) or A₁ and A_(2B) or A₁, A_(2A) and A_(2B) receptoractivity in mammals which method comprises administering to a mammal inneed thereof a therapeutically effective amount of compound of formulaII or its tautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof.

The present invention also provides a method of prophylactic ortherapeutic treatment of disease or discoreder susceptible toimprovement by antagonism of adenosine receptor comprising administeringan effective amount of compound of formula I or its tautomers,polymorphs, stereoisomers, prodrugs, solvate or a pharmaceuticallyacceptable salts thereof, to a mammal in need of such treatment.

The present invention further provides a method of prophylactic ortherapeutic treatment of disease or discoreder susceptible toimprovement by antagonism of adenosine receptor comprising administeringan effective amount of compound of formula II or its tautomers,polymorphs, stereoisomers, prodrugs, solvate or a pharmaceuticallyacceptable salts thereof, to a mammal in need of such treatment.

As used throughout the specification and in the claims, the term“treatment” embraces all the different forms or modes of treatment asknown to those of the pertinent art and in particular includespreventive, curative, delay of progression and palliative treatment.

The term “therapeutically effective amount” as used herein refers to anamount of a drug or a therapeutic agent that will elicit the desiredbiological or medical response of a tissue, system or an animal(including man) that is being sought by a researcher or clinician.

The term “mammal” or “patient” are used interchangeably herein andinclude, but are not limited to, humans, dogs, cats, horses, pigs, cows,sheep, monkeys, rabbits, mice and laboratory animals. The preferredmammals are humans.

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of thepresent invention, alone or in combination with one or morepharmaceutically acceptable carriers.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, for the treatment ofconditions mediated by the adenosine A_(2A) receptor or adenosine A_(2B)receptor. Such conditions include, but are not limited to, asthma,chronic obstructive pulmonary disorder, angiogenesis, pulmonaryfibrosis, emphysema, allergic diseases, inflammation, reperfusioninjury, myocardial ischemia, atherosclerosis, hypertension, congestiveheart failure, retinopathy, diabetes mellitus, obesity, inflammatorygastrointestinal tract disorders, and/or autoimmune diseases.

Generally, the concentration of the compound(s) of the present inventionin a liquid composition, such as a lotion, will be from about 0.01-about25 wt %, preferably from about 0.1-about 10 wt %. The concentration in asemi-solid or a solid composition such as a gel or a powder will beabout 0.1-about 5 wt %, preferably about 0.5-about 25 wt %.

The amount of a compound of the present invention required for use intreatment will vary not only with the particular salt selected but alsowith the route of administration, the nature of the condition beingtreated and the age and condition of the patient and will be ultimatelyat the discretion of the administering physician or clinician. Ingeneral, a suitable dose will be in the range of from about 0.001mg/kg/day to about 20 mg/kg/day For example, a dosage may be from about0.002 mg/kg to about 10 mg/kg of body weight per day, from about 0.01mg/kg/day to about 1 mg/kg/day, and from about 0.1 mg/kg/day to about 5mg/kg/day.

The compound is conveniently administered in unit dosage form, e.g,containing 5 to 1000 μg, about 10 to about 750 μg, about 50 to about 500μg of active ingredient per unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye. Dosages above or belowthe range cited herein above are within the scope of the presentinvention and may be administered to the individual patient if desiredand necessary.

Accordingly, in various embodiments, the present invention providespharmaceutical compositions as described above for the treatment ofconditions mediated by adenosine receptor, such as asthma, chronicobstructive pulmonary disorder, angiogenesis, pulmonary fibrosis,emphysema, allergic diseases, inflammation, reperfusion injury,myocardial ischemia, atherosclerosis, hypertension, congestive heartfailure, retinopathy, diabetes mellitus, obesity, inflammatorygastrointestinal tract disorders, and/or autoimmune diseases.

In various embodiments, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the invention in combination with a therapeutically effective amountof another therapeutic agent, preferably selected from anti-inflammatoryagents, anti-diabetic agents, anti-hypertensive agents andanti-dyslipidemic agents.

According to an embodiment, the pharmaceutical compositions may containa therapeutically effective amount of a compound of the invention asdefined above, either alone or in a combination with another therapeuticagent, e.g., each at an effective therapeutic dose as reported in theart. Such therapeutic agents include: a) anti-inflammatory agents, suchas anticholinergic or antimuscarinic agents; steroids; LTB₄ (leukotrieneB₄) antagonists; dopamine receptor agonists; PDE₄ (phosphodiesterase 4)inhibitors; and beta-2 adrenergic receptor agonists; b) anti-diabeticagents, such as insulin, insulin derivatives and mimetics; insulinsecretagogues; insulinotropic sulfonylurea receptor ligands;thiazolidone derivatives; GSK3 (glycogen synthase kinase-3) inhibitors;sodium-dependent glucose co-transporter inhibitors; glycogenphosphorylase A inhibitors; biguanides; alpha-glucosidase inhibitors;GLP-1 (glucagon like peptide-1), GLP-1 analogs and GLP-1 mimetics;modulators of PPARs (peroxisome proliferator-activated receptors); DPPIV(dipeptidyl peptidase IV) inhibitors; SCD-1 (stearoyl-CoA desaturase-1)inhibitors; DGAT1 and DGAT2 (diacylglycerol acyltransferase 1 and 2)inhibitors; ACC2 (acetyl CoA carboxylase 2) inhibitors; and breakers ofAGE (advanced glycation end products); c) anti-hypertensive agents, suchas loop diuretics; angiotensin converting enzyme (ACE) inhibitors;inhibitors of the Na—K-ATPase membrane pump such as digoxin;neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors; angiotensinII antagonists; renin inhibitors; β-adrenergic receptor blockers;inotropic agents; calcium channel blockers; aldosterone receptorantagonists; and aldosterone synthase inhibitors; and d)anti-dyslipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A(HMG-CoA) reductase inhibitors; HDL increasing compounds such ascholesterol ester transfer protein (CETP) inhibitors; squalene synthaseinhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor)ligands; cholestyramine; fibrates; nicotinic acid; and aspirin.

According to another embodiment, the present invention providespharmaceutical compositions comprising a therapeutically effectiveamount of a compound of formula I of the invention for the treatment ofcancer such as cancers of the lung, liver, breast, pancreas, thyroid,skin, central nervous system, larynx, gastrointestine, colon, rectum,bladder, vascular endothelium, esophagus, colorectal, renal, prostate,cervical, ovaries, and endometrial, melanoma, squamous cell and basalcell carcinoma.

According to yet another embodiment, the present invention providespharmaceutical compositions comprising a therapeutically effectiveamount of a compound of formula II for the treatment of cancer such ascancers of the lung, liver, breast, pancreas, thyroid, skin, centralnervous system, larynx, gastrointestine, colon, rectum, bladder,vascular endothelium, esophagus, colorectal, renal, prostate, cervical,ovaries, and endometrial, melanoma, squamous cell and basal cellcarcinoma.

According to yet another embodiment, the present invention providespharmaceutical compositions comprising a therapeutically effectiveamount of a compound of formula I, for the treatment of Parkinson'sdisease either alone or in a combination with another therapeutic agent,e.g., each at an effective therapeutic dose as reported in the art. Suchtherapeutic agents include: L-DOPA, dopaminergic agonists, MAO-Binhibitors, DOPA decarboxylase inhibitors andcatechol-O-methyltransferase (COMT) inhibitors.

In an another embodiment, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula II, for the treatment of Parkinson's disease either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include: L-DOPA, dopaminergic agonists, MAO-B inhibitors, DOPAdecarboxylase inhibitors and catechol-O-methyltransferase (COMT)inhibitors.

As described above, a compound of the present invention may beadministered either simultaneously, before or after another activeingredient, either separately by the same or different route ofadministration or together in the same pharmaceutical formulation.

The present invention further relates to pharmaceutical compositions asdescribed above for use as a medicament.

The present invention further relates to use of pharmaceuticalcompositions or combinations as described above for the preparation of amedicament for the treatment of conditions mediated by adenosinereceptor, such as asthma, chronic obstructive pulmonary disorder,angiogenesis, pulmonary fibrosis, emphysema, allergic diseases,inflammation, reperfusion injury, myocardial ischemia, atherosclerosis,hypertension, congestive heart failure, retinopathy, diabetes mellitus,obesity, inflammatory gastrointestinal tract disorders, and/orautoimmune diseases.

According to an embodiment, the present invention provides use ofcompound of formula (I) for the treatment of conditions mediated byadenosine receptor.

Further, in another embodiment, the present invention provides use ofcompound of formula II for the treatment of conditions mediated byadenosine receptor.

According to an embodiment, the present invention provides use ofcompound of formula (I) for the treatment of asthma, chronic obstructivepulmonary disorder, angiogenesis, pulmonary fibrosis, emphysema,allergic diseases, inflammation, reperfusion injury, myocardialischemia, atherosclerosis, hypertension, congestive heart failure,retinopathy, diabetes mellitus, obesity, inflammatory gastrointestinaltract disorders, autoimmune diseases. Parkinson's disease, Alzheimer'sdisease, restless leg syndrome, nocturnal myoclonus, cerebral ischaemia,Huntington's disease, Wilson's disease, multiple system atrophy and/orcorticobasal degeneration.

Further, in another embodiment, it provides use of compound of formula(II) for the treatment of asthma, chronic obstructive pulmonarydisorder, angiogenesis, pulmonary fibrosis, emphysema, allergicdiseases, inflammation, reperfusion injury, myocardial ischemia,atherosclerosis, hypertension, congestive heart failure, retinopathy,diabetes mellitus, obesity, inflammatory gastrointestinal tractdisorders, autoimmune diseases. Parkinson's disease, Alzheimer'sdisease, restless leg syndrome, nocturnal myoclonus, cerebral ischaemia,Huntington's disease, Wilson's disease, multiple system atrophy and/orcorticobasal degeneration.

According to an embodiment, the present invention provides use ofcompound of formula (I) for use in preparation of medicament useful inthe treatment of conditions mediated by adenosine receptor.

According to an embodiment, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula II, or its tautomers, polymorphs,stereoisomers, prodrugs, solvate or a pharmaceutically acceptable saltsthereof, for the treatment of asthma, chronic obstructive pulmonarydisorder, angiogenesis, pulmonary fibrosis, emphysema, allergicdiseases, inflammation, reperfusion injury, myocardial ischemia,atherosclerosis, hypertension, congestive heart failure, retinopathy,diabetes mellitus, obesity, inflammatory gastrointestinal tractdisorders, autoimmune diseases, Parkinson's disease, Alzheimer'sdisease, restless leg syndrome, nocturnal myoclonus, cerebral ischaemia,Huntington's disease, Wilson's disease, multiple system atrophy and/orcorticobasal degeneration.

According to another embodiment, the present invention provides apharmaceutical composition comprising a compound of formula II, or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, in combination with one ormore pharmaceutically acceptable therapeutically active agent. Thepharmaceutically acceptable therapeutically active agent is selectedfrom anti-inflammatory agent, anti-diabetic agent, anti-hypertensiveagent, anti-dyslipidemic agent, anticholinergic agent, antimuscarinicagent, steroid, LTB4 (leukotriene B4) antagonist, dopamine receptoragonists, phosphodiesterase 4 inhibitor, beta-2 adrenergic receptoragonist, insulin, insulin derivatives and mimetics, insulinsecretagogues, insulinotropic sulfonylurea receptor ligands,thiazolidone derivatives, glycogen synthase kinase-3 inhibitor,sodium-dependent glucose co-transporter inhibitor, glycogenphosphorylase A inhibitor, biguanide, alpha-glucosidase inhibitor,glucagon like peptide-1 (GLP-1), GLP-1 analogs and GLP-1 mimetics,modulators of peroxisome proliferator-activated receptors, dipeptidylpeptidase IV inhibitor, stearoyl-CoA desaturase-1 inhibitor,diacylglycerol acyltransferase 1 and 2 inhibitor, acetyl CoA carboxylase2 inhibitor, and breakers of advanced glycation end products, loopdiuretics, angiotensin converting enzyme inhibitor, inhibitor of theNa—K-ATPase membrane pump such as digoxin, neutralendopeptidase (NEP)inhibitor, ACE/NEP inhibitors, angiotensin II antagonists, renininhibitors, β-adrenergic receptor blockers, inotropic agents, calciumchannel blockers, aldosterone receptor antagonists, and aldosteronesynthase inhibitors, 3-hydroxy-3-methyl-glutaryl coenzyme A reductaseinhibitor, HDL increasing compounds such as cholesterol ester transferprotein inhibitor, squalene synthase inhibitor, farnesoid X receptor andliver X receptor ligand, cholestyramine, fibrates, nicotinic acid, oraspirin.

Further, in another embodiment, it provides use of compound of formula(II) for use in preparation of medicament useful in the treatment ofasthma, chronic obstructive pulmonary disorder, angiogenesis, pulmonaryfibrosis, emphysema, allergic diseases, inflammation, reperfusioninjury, myocardial ischemia, atherosclerosis, hypertension, congestiveheart failure, retinopathy, diabetes mellitus, obesity, inflammatorygastrointestinal tract disorders, and/or autoimmune diseases.

EXAMPLES

The invention is further illustrated by the following examples which inno way should be construed as being further limiting. One skilled in theart will readily appreciate that the specific methods and resultsdescribed are merely illustrative. Structures of the intermediates aswell as the final compounds were confirmed by nuclear magnetic resonancespectra for proton (¹H NMR) and LCMS.

Example 18-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-1,4,5,7-tetrahydro-purin-6-one

Step 1: 1-Benzyl-1H-pyrazole-4-carboxylic acid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide

A mixture of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (1.6 g, 8.55mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (1.75 g, 8.65 mmol) inmethanol (10 ml) were cooled to 0° C. and added EDCI.HCl (2.32 g, 12.11mmol). The reaction mixture was stirred at 25° C. for 20 hours and thesolvents were removed under reduced pressure. To this residue water (10ml) was added and the precipitate was filtered off, and was washedsequentially with cold water (20 ml) and DCM (25 ml) to obtain1-Benzyl-1H-pyrazole-4-carboxylic acid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide(1.5 g, 47%) as a pale yellow solid.

¹HNMR (400 MHz, DMSO d6): δ 0.82 (t, J=7.6 Hz, 3H); 1.46-1.51 (m, 2H);3.64 (t, J=7.2 Hz, 2H); \ 5.36 (s, 2H); 6.01 (s, 2H); 7.26-7.38 (m, 5H);7.96 (s, 1H); 8.31 (s, 1H); 8.54 (s, 1H); 10.43 (s, 1H).

Step 2:8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one

A mixture of1-benzyl-1H-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide(0.5 g, 13.5 mmol), POCl₃ (10 ml) and DMF (0.1 ml) were heated at125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. Itwas then concentrated under vacuum. The residue was triturated withdiethyl ether, dried. The crude product was purified by columnchromatography using silica gel (100-200 mesh) and 2 to 4% methanol inDCM as an eluent to obtain8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one(0.04 g, 8%) as a pale brown solid.

¹HNMR (400 MHz, DMSO d6): δ 0.93 (t, J=7.6 Hz, 3H); 1.67-1.73 (m, 2H);4.15 (t, J=7.6 Hz, 2H); 5.42 (s, 2H); 7.29-7.39 (m, 5H); 8.14 (s, 1H);8.49 (s, 1H); 13.68 (bs, 1H).

Step 3: 8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one

A mixture of8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one(0.035 g, 0.094 mmol), Pd\C (10%) (0.025 g), in ethanol (20 ml) werestirred under hydrogen atmosphere for 20 hours. Reaction mixture wasfiltered through celite bed washed with methanol (20 ml), and thesolvents were removed under vacuum. The crude product was purified bycolumn chromatography using silica gel (100-200 mesh) and 2 to 4%methanol in DCM as an eluent to obtain8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.012 g,39%) as off white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.89 (t, J=7.2 Hz, 3H); 1.66-1.72 (m, 2H);3.94 (t, J=7.6 Hz, 2H); 5.41 (s, 2H); 7.302-7.38 (m, 5H); 8.03 (s, 1H);8.16 (s, 1H); 8.34 (s, 1H).

Example 22-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one

A mixture of1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide(0.8 g, 1.76 mmol), POCl₃ (25 ml) and PCl₅ (0.2 g) were heated at125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. andit was concentrated under vacuum. To this reaction mixture brine (50 ml)was added and extracted with ethyl acetate (3×2 ml). The combinedorganic layer was dried over Na₂SO₄ and evaporated to dryness. The crudeproduct was purified by column chromatography using silica gel (100-200mesh) and 2 to 4% methanol in DCM as an eluent to obtain2-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one(0.4 g, 50%) as a pale brown solid.

¹HNMR (400 MHz, CD₃OD): δ 1.05 (t, J=7.2 Hz, 3H); 1.83-1.85 (m, 2H);4.31 (t, J=5.6 Hz, 2H); 5.57 (s, 2H); 7.26-7.29 (m, 2H); 7.70-7.74 (m,1H); 8.16 (s, 1H); 8.40 (s, 1H).

Examples 3-7 were prepared in an analogous manner of Example 2 fromappropriate intermediates.

Example IUPAC name 32-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 42-Chloro-8-[1-(3-fluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one 52-Chloro-8-[1-(2,4-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one 62-Chloro-8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one 72-Chloro-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Example 88-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one

A mixture of2-Chloro-8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one(0.04 g, 0.09 mmol), ammonium formate (0.134 g, 1.97 mmol), Pd\C (10%)(0.02 g), DMF (2 ml) and H₂O (0.5 ml) were heated at 85-90° C. for 15hours. Reaction mixture was cooled to 20-25° C. and then it was filteredthrough celite bed washed with methanol (10 ml). The filtrate wasconcentrated under vacuum. To this residue water (1 ml) was added andacidified with citric acid up to pH (1-2). Solid precipitated wasfiltered off and washed sequentially with cold water, diethyl ether toobtain pure8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one(0.01 g, 28%) as a off white solid.

¹HNMR (400 MHz, CD₃OD): δ 0.98 (t, J=7.2 Hz, 3H); 1.78-1.84 (m, 2H);4.06 (t, J=6.8 Hz, 2H); 5.54 (s, 2H); 7.08-7.11 (m, 1H); 7.15-7.18 (m,1H); 7.26-7.29 (m, 1H); 8.11 (s, 1H); 8.25 (s, 1H); 8.35 (s, 1H).

Examples 9-13 were prepared in an analogous manner of Example 8 fromappropriate intermediates.

Example IUPAC name 98-[1-(3-Fluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one, 108-[1-(2,4-Difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one 111-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 121-Propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 138-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one

Example 14 1-Propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one

Step 1:8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one(0.9 g, 2.44 mmol), K₂CO₃ (1.01 g, 7.32 mmol) in DMF (10 ml) were cooledto 0° C. and added SEM-Cl (1.3 ml, 7.32 mmol). The reaction mixture wasstirred at 25° C. for 20 hours. To this reaction mixture water (100 ml)was added and extracted with ethyl acetate (3×30 ml). The combinedorganic layer was washed with brine (30 ml) and dried over Na₂SO₄. Theorganic layer was evaporated to dryness and the crude product waspurified by column chromatography using silica gel (100-200 mesh) and10-15% ethyl acetate in hexane as an eluent to obtain8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.3 g, 25%) as a off white solid.

¹HNMR (400 MHz, CDCl₃): δ −0.01 (s, 9H); 0.94 (t, J=8.4 Hz, 3H); 1.04(t, J=7.6 Hz, 2H); 1.79-1.85 (m, 2H); 3.77 (t, J=8.0 Hz, 2H); 4.28 (t,J=7.6 Hz, 2H); 5.40 (s, 2H); 5.86 (s, 2H); 7.31-7.41 (m, 5H); 8.28 (s,1H); 8.35 (s, 1H).

Step 2: 1-Propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one

A mixture of8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.1 g, 0.201 mmol), Pd(OH)₂ (20%) (0.2 g), in ethanol (4 ml) andcyclohexene were stirred under nitrogen balloon for 25 hrs. Reactionmixture was filtered through celite bed washed with methanol (20 ml).The filtrate was concentrated under vacuum and the crude product waspurified by column chromatography using silica gel (100-200 mesh) and 5to 6% methanol in DCM as an eluent to obtain1-propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one (0.018 g, 24%) aswhite solid.

¹HNMR (400 MHz, CD₃OD): δ 1.02 (t, J=7.2 Hz, 3H); 1.82-1.88 (m, 2H);4.10 (t, J=7.6 Hz, 2H); 8.20 (bs, 1H); 8.29 (bs, 1H); 8.36 (bs, 1H).

Example 15 8-(4-Hydroxy-phenyl)-1-propyl-1,7-dihydro-purin-6-one

Preparation of 4-benzyloxy-benzoic acid methyl ester

A mixture of methyl 4-hydroxy-benzoate (10.0 g, 0.066 mol) and potassiumcarbonate (12 g, 0.086 mol), were taken in acetone (50 ml) and heated at50° C. for 1 hour. To the reaction mixture benzyl bromide (8.2 ml, 0.072mol) was added. The mixture was heated at 80° C. for 5 hours. Themixture was cooled to room temperature and filtered through sinteredfunnel, washed with acetone. Solvent was removed to obtain pure4-benzyloxy-benzoic acid methyl ester as white solid (16 g, 100%).

¹HNMR (400 MHz, CDCl₃): δ 3.85 (s, 3H); 5.17 (s, 2H); 6.99 (d, J=8.8 Hz,2H); 7.38-7.42 (m, 5H); 8.00 (d, J=8.8 Hz, 2H)

Preparation of 4-benzyloxy-benzoic acid

The above product (19.0 g, 0.074 mol) was dissolved in a mixture ofsolvents THF:methanol:water (3:2:1, 250 ml) and NaOH (5.9 gm, 0.15 mol)was added to the reaction mixture and stirred at 50-55° C. for 3 hours.Solvents were removed and the residue was diluted with water (20 ml),washed with hexane (2×50 ml) and acidified with dil. HCl to obtain whiteprecipitate, 4-benzyloxy-benzoic acid (15 g, 89%).

¹HNMR (400 MHz, CDCl₃): δ 5.14 (s, 2H); 7.02 (d, J=8.8 Hz, 2H); 7.4-7.42(m, 5H); 8.05 (d, J=8.8 Hz, 2H).

Step 1:N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide

A mixture of 4-benzyloxy-benzoic acid (7.44 g, 0.033 mol),5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (5.0 g, 0.027 mol),methanol (60 ml), EDCI (10.0 g, 0.052 mol), were taken and stirred for20 hours at 20-25° C. The reaction mixture was concentrated and water(50 ml) was added to obtain solid precipitate. The compound was purifiedby column chromatography to obtainN-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamideas light yellow solid (4.0 g, 38%).

¹HNMR (400 MHz, DMSO d6): δ 0.82-0.90 (m, 3H); 1.47-1.49 (m, 2H); 3.65(t, J=6.8 Hz, 2H); 5.19 (s, 2H); 6.04 (s, 2H); 7.08 (d, J=8.4 Hz, 2H);7.32-7.48 (m, 5H); 7.93 (d, J=8.4 Hz, 2H); 8.75 (s, 1H); 10.44 (s, 1H).

Step 2: 8-(4-Benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one

The aboveN-(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide(1.0 g, 0.0025 mol) and phosphorous pentachloride (0.64 g, 0.0025 mol)were taken in phosphorous oxy chloride (25 ml) and refluxed for 20 hoursThe mixture was cooled and solvent was removed. The residue wasdissolved in water (20 ml) and extracted with DCM (3×5 ml). The organiclayer was washed with sat.NaHCO₃ (30 ml) followed by saturated brinesolution (2×30 ml) and dried over Na₂SO₄. Solvent was removed and theresidue was further purified by column chromatography to obtain pure8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298g, 30%) as a yellow solid.

¹HNMR (400 MHz, DMSO d6): δ 0.82-0.90 (m, 3H); 1.47-1.49 (m, 2H); 3.65(t, J=6.8 Hz, 2H); 5.19 (s, 2H); 6.04 (s, 2H); 7.08 (d, J=8.4 Hz, 2H);7.32-7.48 (m, 5H); 7.93 (d, J=8.4 Hz, 2H); 8.75 (s, 1H); 10.44 (s, 1H).

Step 3:8-(4-Benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.298g, 0.00075 mol) and potassium carbonate (0.311 g, 0.0023 mol), weretaken in DMF (2 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (0.4 ml,0.0023 mol) was added drop wise at 0° C. and the mixture was stirred at20° C. for 4 hours. The mixture was cooled to 10° C. and diluted withwater (10 ml). The aqueous layer was extracted with ethyl acetate (2×10ml). The organic layer was washed with saturated brine solution (2×15ml) and dried over Na₂SO₄. Solvent was removed and the residue wasfurther purified by column chromatography to obtain pure8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.278 g, 70%) as off white solid.

¹HNMR (400 MHz, DMSO d6): δ −0.01 (s, 9H); 0.84-0.86 (m, 2H); 0.93 (t,J=7.6 Hz, 3H); 1.67-1.71 (m, 2H); 3.67 (t, J=8 Hz, 2H); 4.18 (t, J=7.6Hz, 2H); 5.21 (s, 2H); 5.73 (s, 2H); 7.21 (d, J=8.8 Hz, 2H); 7.34-7.42(m, 5H); 7.92 (d, J=8.8 Hz, 2H)

Step 4:8-(4-Hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

To a solution of8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.25 g, 0.00048 mol) in DMF:water nil), 10% Pd/C (0.130 g) and ammoniumformate (0.66 g, 0.010 mol) were added and refluxed at 80° C. for 2hours. The mixture was cooled and filtered through celite bed, solventwas removed and the residue was diluted with water (10 ml), acidifiedwith citric acid and extracted with ethyl acetate (3×10 ml). The organiclayer was washed with brine (2×15 ml). It was dried over Na₂SO₄ and thesolvent was removed to obtain pale yellow solid of8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.153 g, 80%).

¹HNMR (400 MHz, DMSO d6): δ −0.01 (s, 9H); 0.83-0.90 (m, 5H); 1.68-1.74(m, 2H); 3.68 (t, J=7.6 Hz, 2H); 3.99 (t, J=6.4 Hz, 2H); 5.76 (s, 2H);6.93 (d, J=8.8 Hz, 2H); 7.82 (d, J=8.8 Hz, 2H); 8.38 (s, 1H); 10.1 (s,1H).

Step 5: 8-(4-Hydroxy-phenyl)-1-propyl-1,7-dihydro-purin-6-one

A mixture of8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.03 g, 0.075 mmol), 2N HCl (1 ml), ethanol (2 ml) was heated at 85° C.for 2 hours. The mixture was cooled and the solvent was evaporated. Theresidue was washed with n-pentane to obtain8-(4-Hydroxy-phenyl)-1-propyl-1,7-dihydro-purin-6-one (0.019 g, 95%) asa yellow solid.

¹HNMR (400 MHz, DMSO d6): δ 0.91 (t, J=7.2 Hz, 3H); 1.70-1.72 (m, 2H);3.98 (t, J=7.2 Hz, 2H); 6.91 (d, J=8.4 Hz, 2H); 8.01 (d, J=8.4 Hz, 2H);8.33 (s, 1H); 10.1 (bs, 1H).

Example 168-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one

Step 1:8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.100 g, 0.25 mmol), potassium carbonate (0.086 g, 0.50 mmol),1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.107 g, 0.50 mmol) were takenin acetone (10 ml). The reaction mixture was heated at 80° C. for 2hour. The mixture was cooled to room temperature and filtered throughsintered funnel, washed with acetone. Solvent was evaporated and theresidue was purified by preparative TLC to obtain pure8-{4-[3-(4-fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.033 g, 25%) as pale yellow solid.

Step 2:8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one

A mixture of8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.03 g, 0.056 mmol), 2N HCl (1 ml), ethanol (2 ml) was heated at 85° C.for 2 hours. The mixture was cooled and the solvent was evaporated. Theresidue was washed with n-pentane to obtain8-{4-[3-(4-fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one(0.018 g, 78%) as off white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.88 (t, J=7.2 Hz, 3H); 1.69-1.70 (m, 2H);3.97 (t, J=7.2 Hz, 2H); 5.12 (s, 2H); 7.17-7.25 (m, 4H); 7.50-7.54 (m,2H); 8.12 (d, J=8.8 Hz, 2H); 8.32 (s, 1H);

Examples 17-20 were prepared in an analogous manner of Example 16 fromappropriate intermediates.

Example IUPAC name 171-Propyl-8-{4-[3-(3-trifluoromethyl-phenyl)-prop-2-ynyloxy]-phenyl}-1,7-dihydro-purin-6-one 188-{4-[5-Oxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-ylmethoxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one 198-{4-[5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethoxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one 20[4-(6-Oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]- acetic acidethyl ester

Example 21N-(4-Cyano-phenyl)-2-[4-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetamide

Step 1: 2-Chloro-N-(4-cyano-phenyl)-acetamide

A mixture of 4-Amino benzonitrile (1.0 g, 0.0084 mol) and triethyl amine(1 ml, 0.010 mol) was taken in DCM (15 ml). Chloro acetyl chloride (0.67ml, 0.0084 mol) was added slowly and stirred for 22 hours at 25-27° C.Solvent was removed and the residue was dissolved in ethyl acetate (20ml), washed with water (1×15 ml) followed by brine (2×15 ml). Theorganic layer was dried over Na₂SO₄ and the solvent was removed to getpure 2-chloro-N-(4-cyano-phenyl)-acetamide (1.51 g, 92%).

¹HNMR (400 MHz, CDCl₃): δ 4.22 (s, 2H); 7.66 (d, J=8.4 Hz, 2H); 7.71 (d,J=8.4 Hz, 2H); 8.38 (bs, 1H).

Step 2:N-(4-Cyano-phenyl)-2-{4-[6-oxo-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-6,7-dihydro-1H-purin-8-yl]-phenoxy}-acetamide

A mixture of8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.100 g, 0.25 mmol), potassium carbonate (0.052 g, 0.38 mmol), and2-chloro-N-(4-cyano-phenyl)-acetamide (0.053 g, 0.28 mmol) in acetone(10 ml) was heated at 80° C. for 2 hours. The mixture was cooled to roomtemperature and filtered through sintered funnel, washed with acetone.The solvent was evaporated and the residue was purified by preparativeTLC to obtain pure pale yellow solid ofN-(4-cyano-phenyl)-2-{4-[6-oxo-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-6,7-dihydro-1H-purin-8-yl]-phenoxy}-acetamide(0.110 g, 79%) as a off white solid.

Step 3:N-(4-cyano-phenyl)-2-[4-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetamide

The above compoundN-(4-Cyano-phenyl)-2-{4-[6-oxo-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-6,7-dihydro-1H-purin-8-yl]-phenoxy}-acetamide(0.110 g, 0.20 mmol) was taken in DCM (6 ml) and TFA (3 ml), stirred for4 hrs at 27° C. The solvent was evaporated and the residue was washedwith saturated NaHCO₃ followed by water and n-pentane to obtainN-(4-cyano-phenyl)-2-[4-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetamide(0.049 g, 58%).

¹HNMR (400 MHz, DMSO d6): δ 0.89 (t, J=7.2 Hz, 3H); 1.68-1.74 (m, 2H);3.98 (t, J=7.2 Hz, 2H); 4.86 (s, 2H); 7.14 (d, J=8.8 Hz, 2H); 7.80-7.86(m, 4H); 8.15-8.28 (m, 2H); 8.31 (s, 1H); 10.58 (s, 1H); 13.58 (bs, 1H).

Similarly, the following compound Example 22 has been made:

Example 228-[4-[2-oxo-2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethoxy]phenyl]-1-propyl-7H-purin-6-oneExample 23 1-Propyl-8-thiophen-2-yl-1,7-dihydro-purin-6-one

Step 1: N*4*-Allyl-6-chloro-pyrimidine-4,5-diamine

A mixture of 5-amino-4,6-dichloro pyrimidine (3.0 g, 0.018 mol) andallyl amine (1.5 ml, 0.020 mol) was taken in ethanol (30 ml) and heatedat 80° C. for 16 hrs. Solvent was removed to get crude product which wasfurther purified by column chromatography to get pureN*4*-Allyl-6-chloro-pyrimidine-4,5-diamine as off white solid (2.30 g,68%).

¹HNMR (400 MHz, CDCl₃): δ 4.16-4.18 (m, 2H); 5.19-5.30 (m, 2H); 5.39 (s,1H); 5.95-6.02 (m, 1H); 8.10 (s, 1H)

Step 2: Thiophene-2-carboxylic acid(4-allylamino-6-chloro-pyrimidin-5-yl)-amide

N*4*-Allyl-6-chloro-pyrimidine-4,5-diamine (0.20 g, 0.0011 mol) wastaken in NMP (3 ml). Thiophene-2-carbonyl chloride (0.14 ml, 0.0013 mol)was added slowly at 0° C. and stirred for 2 hrs at same temperature. Thereaction mixture was diluted with water (10 ml) and extracted with DCM(3×5 ml). The organic layer was washed with saturated NaHCO₃ solution(10 ml), followed by brine (10 ml) and dried over Na₂SO₄. The solventwas removed to get thiophene-2-carboxylic acid(4-allylamino-6-chloro-pyrimidin-5-yl)-amide (0.281 g, 88%) as a paleyellow solid.

Step 3: 9-Allyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one

The above compound (0.281 g, 0.95 mmol) was taken in a mixture ofisopropanol (5 ml) and sulfuric acid (1 ml) and refluxed for 22 hours at110° C. Solvent was removed and the residue was diluted with water (2ml), and basified with Na₂CO₃. The aqueous layer was extracted withCHCl₃ (3×5 ml). The organic layer was washed with brine (10 ml), driedover Na₂SO₄. The solvent was evaporated and the crude product waspurified by preparative TLC to get9-Allyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 41%).

Step 4: 9-Allyl-1-propyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one

A mixture of 9-Allyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g,0.39 mmol), n-propyl iodide (0.04 ml, 0.4 mmol) and Cs₂CO₃ (0.192 g,0.59 mmol) were taken in DMF (1 ml) and stirred for 20 hours at 27° C.The reaction mixture was diluted with water (5 ml) and extracted withethyl acetate (3×10 ml). The organic layer was washed with brine (2×15ml), dried over Na₂SO₄. Solvent was removed to get9-allyl-1-propyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 86%).

Step 5: 1-Propyl-8-thiophen-2-yl-1,7-dihydro-purin-6-one

The above compound,9-allyl-1-propyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 0.33mmol) and Wilkinson's catalyst were taken in acetonitrile:water (6:1, 7ml) and refluxed for 5 h at 100° C. Solvent was removed and furtherpurified by preparative TLC to get pure1-propyl-8-thiophen-2-yl-1,7-dihydro-purin-6-one (9 mg, 10%).

¹HNMR (400 MHz, DMSO d6): δ 0.79-0.86 (m, 3H); 1.63-1.67 (m, 2H);3.90-3.94 (m, 2H); 7.16-7.18 (m, 1H); 7.65-7.71 (m, 1H); 7.92-7.93 (m,1H); 8.28-8.31 (m, 1H); 13.23 (bs, 1H)

Example 248-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one

Step 1:8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(50.0 mg, 0.96 mmol), 3-Trifluoromethyl phenyl boronic acid (31.0 mg,1.4 mmol) were taken in THF (5 ml) and degassed for 10 minutes. To abovedegassed solution NaHCO₃ (20.0 mg, 0.24 mmol) in water (1 ml) andPd(PPh₃)₄ were added and degassed for another 20 minutes. The reactionmixture was stirred for 28 hours at 80-90° C. The mixture was cooled to25-27° C. and diluted with water (5 ml). The aqueous layer was extractedwith DCM (3×5 ml). The organic layer was washed with brine (2×10 ml),dried over Na₂SO₄, and the solvent was evaporated. The residue obtainedwas purified by preparative TLC (35% Ethyl acetate in hexane) to obtainpure8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(68 mg, quantitative) as a yellow solid.

¹HNMR (400 MHz, DMSO d6): −0.01 (s, 9H); 0.71-0.73 (m, 2H); 0.97-0.99(m, 3H); 1.57-2.02 (m, 2H); 3.80 (t, J=7.6 Hz, 2H); 3.88-3.91 (m, 2H);5.28 (s, 2H); 5.88 (s, 2H); 7.29 (d, J=8 Hz, 2H); 7.41-7.50 (m, 3H);7.55 (d, J=8 Hz, 2H); 7.86-7.89 (m, 2H); 7.98-8.01 (m, 3H); 8.11 (s, 1H)

Step 2:8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one

Step-2 was carried out as described in Step-2 of Example 16

¹HNMR (400 MHz, DMSO d6): 0.66 (t, J=6.8 Hz, 3H); 1.51-1.58 (m, 2H);3.85 (t, J=6.8 Hz, 2H); 5.2 (s, 2H); 7.19 (d, J=8.4 Hz, 2H); 7.36-7.42(m, 3H); 7.49 (d, J=6.8 Hz, 2H); 7.81-7.83 (m, 1H); 7.91-7.98 (m, 2H);8.06 (s, 1H); 8.12 (d, J=7.6 Hz, 2H)

Example 258-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one

Step 1:8-(4-Hydroxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

To a solution of8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.217 g, 0.24 mmol) in DMF:water (2.5 ml), 10% Pd/C (0.120 g) andammonium formate (0.431 g, 6.8 mmol) were added and refluxed at 80° C.for 2 hours. The mixture was cooled and filtered through celite bed,solvent was evaporated and the residue was diluted with water (10 ml),acidified with citric acid and extracted with ethyl acetate (3×10 ml).The organic layer was washed with brine (2×15 ml). It was dried overNa₂SO₄ and the solvent was evaporated to obtain off white solid of8-(4-Hydroxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.237 g, quantitative).

¹HNMR (400 MHz, DMSO d6): δ −0.01-(−0.015) (s, 9H); 0.64-0.66 (m, 2H);0.84-0.90 (m, 3H); 1.50-1.52 (m, 2H); 3.72 (t, J=7.6 Hz, 2H); 3.81-3.83(m, 2H); 5.79 (s, 2H); 6.93 (d, J=8.4 Hz, 2H); 7.81-7.83 (m, 3H); 7.94(d, J=7.6 Hz, 2H); 8.0. (s, 1H); 10.12 (s, 1H).

Step 2:8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of8-(4-Hydroxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.115 g, 0.21 mmol), potassium carbonate (0.067 g, 0.48 mmol),1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.67 g, 0.27 mmol) and acetone(10 ml) was heated at 60° C. for 2 hours. The mixture was cooled to roomtemperature and filtered through sintered funnel, washed with acetone.Solvent was evaporated and the residue was purified by preparative TLCto obtain pure8-{4-[3-(4-Fluoro-Phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.061 g, 43%) as pale yellow oil.

¹HNMR (400 MHz, DMSO d6): δ −0.015 (s, 9H); 0.72 (t, J=6.8 Hz, 2H);0.91-0.98 (m, 3H); 1.54-1.60 (m, 2H); 3.80 (t, J=8.4 Hz, 2H); 3.88-3.91(m, 3H); 5.22 (s, 2H); 5.90 (s, 2H); 7.30-7.33 (m, 4H); 7.58-7.61 (m,2H); 7.86-7.89 (m, 1H); 8.01-8.05 (m, 4H); 8.11 (s, 1H).

Step 3:8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one

A mixture of8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.056 g, 0.083 mmol), 2N HCl (2 ml), ethanol (2 ml) was heated at 85°C. for 2 hours. The mixture was cooled and the solvent was evaporated.The residue was washed with n-pentane to obtain8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one(0.021 g, 46%) as an off white solid.

¹HNMR (400 MHz, DMSO d6): δ −0.16-(−0.96) (m, 3H); 0.72-0.81 (m, 2H);3.04-3.06 (m, 2H); 4.37 (s, 2H); 6.43-6.47 (m, 4H); 6.75-6.77 (m, 2H);7.02-7.04 (m, 1H); 7.16-7.18 (m, 2H); 7.27-7.29 (m, 2H); 7.41-7.43 (m,1H); 12.9-13 (bs, 1H).

Example 268-(4-Methoxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one

Obtained following analogous procedure of Example 25 starting fromappropriate intermediates.

¹HNMR (400 MHz, DMSO d6): δ −0.67 (t, J=7.6 Hz, 3H); 1.51-1.55 (m, 2H);3.41 (m, 2H); 3.84 (s, 3H); 7.11 (d, J=8.8 Hz, 2H); 7.80-7.83 (m, 1H);7.94-7.97 (m, 2H); 8.06 (s, 1H); 8.13 (d, J=8.4 Hz, 2H).

Example 278-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one

Step 1:8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one

A mixture of8-(1-benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one(prepared as given in Example 1) (1.2 g, 3.2 mmol), pyrrolidine (0.34 g,4.8 mmol), Di-isopropyl ethyl amine (0.826 g, 6.4 mmol) andN-methylpyrrolidone (12 ml) were heated at 80-90° C. for 20 hours.Reaction mixture was cooled to 20-25° C. and water (20 ml) was added,solid separated out. The solid material was filtered off and purified bycolumn chromatography to get pure8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-oneas off white solid (0.83 g, 64%).

¹HNMR (400 MHz, DMSO d6): δ 0.80-0.86 (m, 3H); 1.66-1.70 (m, 2H);1.87-1.94 (m, 4H); 3.29-3.32 (m, 2H); 3.41-3.44 (m, 2H); 4.01-4.04 (m,2H); 5.4 (s, 2H); 7.28-7.39 (m, 5H); 8.02 (s, 1H); 8.3 (s, 1H); 13.03(s, 1H)

Step 2:8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one(0.83 g, 2.1 mmol) and potassium carbonate (0.857 g, 6.2 mmol) was takenin DMF (5 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (1.0 ml, 6.2mmol) was added drop wise at 0° C. and the mixture was stirred at 20° C.for 4 hours. The mixture was cooled to 10° C. and diluted with water (10ml). The aqueous layer was extracted with ethyl acetate (3×15 ml). Theorganic layer was washed with saturated brine solution (2×15 ml) anddried over Na₂SO₄. Solvent was evaporated and the residue was furtherpurified by column chromatography to obtain the above product as paleyellow semisolid (0.325 g, 30%)

¹HNMR (400 MHz, DMSO d6): δ −0.004-(−0.01) (m, 9H); 0.9-0.97 (m, 5H);1.75-1.80 (m, 2H); 1.96-2.0 (m, 4H); 3.40-3.44 (m, 2H); 3.50-3.56 (m,2H); 3.74 (t, J=8 Hz, 2H); 4.12-4.14 (m, 2H); 5.55 (s, 2H); 5.91 (s,2H); 7.41-7.48 (m, 5H); 8.12 (s, 1H); 8.52 (s, 1H).

Step 3:1-Propyl-8-(1H-pyrazol-4-yl)-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.154 g, 0.29 mmol), and DMSO (0.2 ml, 2.9 mmol) was taken in THF (10ml). 0.5M solution of KO^(t)Bu (4 ml, 2.0 mmol) in THF was added at 0°C. and stirred for 18 hours. After adding saturated NH₄Cl solution, thecompound was extracted with ethyl acetate (2×10 ml). Organic layer waswashed with brine (2×10 ml), dried over Na₂SO₄. Solvent was evaporatedand purified by preparative TLC to get pure1-Propyl-8-(1H-pyrazol-4-yl)-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-oneas white solid (89 mg, 70%)

¹HNMR (400 MHz, DMSO d6): δ −0.004-(−0.01) (m, 9H); 0.88-0.97 (m, 5H);1.74-1.80 (m, 2H); 1.96-2.0 (m, 4H); 3.40-3.44 (m, 2H); 3.50-3.52 (m,2H); 3.74 (t, J=7.6 Hz, 2H); 4.12 (t, J=6.8 Hz, 2H); 5.90 (s, 2H); 8.25(s, 2H)

Step 4:8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of1-Propyl-8-(1H-pyrazol-4-yl)-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.111 g, 0.25 mmol), potassium carbonate (0.052 g, 0.38 mmol),1-(3-bromo-prop-1-ynyl)-4-fluoro-benzene (0.69 g, 0.33 mmol) was takenin acetone (10 ml). The reaction mixture was heated at 80° C. for 2hours. The mixture was cooled to room temperature and filtered throughsintered funnel, washed with acetone. Solvent was evaporated and theresidue was purified by preparative TLC to obtain pure8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.025 g, 22%) as colourless oil.

Step 5:8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one

A mixture of8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(0.025 g, 0.043 mmol), 2N HCl (0.5 ml), ethanol (2 ml) was heated at 85°C. for 2 hours. The mixture was cooled and the solvent was evaporated.The residue was washed with n-pentane to obtain pure8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one(0.021 g, quantitative) as yellow solid.

¹HNMR (400 MHz, DMSO d6): δ 0.92 (t, J=7.6 Hz, 3H); 1.75-1.80 (m, 2H);1.99-2.02 (m, 4H); 3.60-3.64 (m, 4H); 4.18 (t, J=7.2 Hz, 2H); 5.38 (s,2H); 7.11-7.15 (m, 2H); 7.52-7.55 (m, 2H); 8.19 (s, 1H); 8.65 (s, 1H).

Example 281-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one

Step 1:N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide

A mixture of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (2.0 g, 11.0mmol), 6-Chloro nicotinic acid (1.86 g, 11.8 mmol) in methanol (40 ml)were cooled to 0° C. and added EDCI.HCl (4.2 g, 22 mmol). The reactionmixture was stirred at 25° C. for 20 hours and the solvents were removedunder reduced pressure. To this residue water (20 ml) was added and theprecipitate was filtered off, and washed sequentially with cold water(20 ml) and methanol (5 ml) to obtainN-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamideas an off white solid. (2.47 g, 70%).

¹HNMR (400 MHz, DMSO d6): δ 0.81 (t, J=7.6 Hz, 3H); 1.45-1.51 (m, 2H);3.64 (t, J=7.2 Hz, 2H); 6.24 (s, 2H); 7.65 (d, J=8.4 Hz, 1H); 8.29 (dd,J=8.4 Hz, 2.4 Hz, 1H); 8.90 (d, J=2 Hz, 1H); 9.17 (s, 1H); 10.54 (s, 1H)

Step 2: 8-(6-Chloro-pyridin-3-yl)-1-propyl-3,7-dihydro-purine-2,6-dione

A mixture ofN-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide(2.47 g, 7.6 mmol), P₂O₅ was taken in DMF (20 ml) and heated at 100-102°C. for 30 minute. Reaction mixture was cooled to room temperature andcold water (60 ml) was added. Precipitated solid was filtered off to get8-(6-Chloro-pyridin-3-yl)-1-propyl-3,7-dihydro-purine-2,6-dione as paleyellow solid (1.8 g, 77%).

¹HNMR (400 MHz, DMSO d6): δ 0.84-0.90 (m, 3H); 1.53-1.59 (m, 2H);3.79-3.09 (m, 2H); 7.69 (d, J=8 Hz, 1H); 8.42 (dd, J=8.8 Hz, 2.4 Hz,1H); 9.04 (d, J=2.4 Hz, 1H); 11.99 (s, 1H); 14.01 (s, 1H)

Step 3:1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-3,7-dihydro-purine-2,6-dione

A mixture of8-(6-Chloro-pyridin-3-yl)-1-propyl-3,7-dihydro-purine-2,6-dione (0.5 g,1.6 mmol) and 3-Trifluoromethyl-benzylamine (3 ml) was stirred in sealedtube for 48 hours at 200° C. Reaction mixture was cooled and filtered,washed with ethanol to get1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-3,7-dihydro-purine-2,6-dioneas off white solid (0.61 g, 84%).

¹HNMR (400 MHz, DMSO d6): δ 0.87 (t, J=7.4 Hz, 31-1); 1.53-1.59 (m, 2H);3.80 (t, J=7.6 Hz, 2H); 4.64 (d, J=6 Hz, 2H); 6.65 (d, J=8.8 Hz, 1H);7.54-7.68 (m, 4H); 7.79 (m, 1H); 8.01-8.04 (dd, J=8 Hz, 2.3 Hz, 1H);8.68 (d, J=2 Hz, 1H); 11.8 (bs, 1H); 13.30 (bs, 1H)

Step 4:2-Chloro-1-propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one

A mixture of1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-3,7-dihydro-purine-2,6-dione(0.2 g, 0.45 mmol), POCl₃ (5 ml) and NH₄Cl (0.486 g, 9 mmol) were heatedat 125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. Itwas then concentrated under vacuum. The residue was dissolved in water(50 ml) and precipitated solid was filtered off. The solid obtained wasfurther purified by column chromatography to obtain pure2-Chloro-1-propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-oneas pale yellow solid (0.054 g, 26%).

¹HNMR (400 MHz, DMSO d6): δ 0.91 (t, J=7.6 Hz, 3H); 1.65-1.71 (m, 2H);4.14 (t, J=7.6 Hz, 2H); 4.63 (d, J=5.2 Hz, 2H); 6.65 (d, J=8.8 Hz, 1H);7.53-7.67 (m, 4H); 7.78 (s, 1H); 8.07 (s, 1H); 8.75 (s, 1H); 13.61 (bs,1H)

Similarly following compounds have been made starting from appropriateintermediates:2-Chloro-8-[6-(3-fluoro-benzylamino)-pyridin-3-yl]-1-propyl-1,7-dihydro-purin-6-one

¹HNMR (400 MHz, DMSO d6): δ 0.94 (t, J=7.6 Hz, 3H); 1.68-1.74 (m, 2H);4.16 (t, J=7.2 Hz, 2H); 4.58 (d, J=6.0 Hz, 2H); 6.65 (d, J=8.8 Hz, 1H);7.04-7.19 (m, 3H); 7.34-7.40 (m, 1H); 7.74 (s, 1H); 8.08 (s, 1H); 8.75(s, 1H); 13.61 (bs, 1H)

Step 5:1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one

A mixture of2-Chloro-1-propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one(0.094 g, 0.2 mmol), Ammonium formate (0.256 g, 0.4 mmol), Pd/C (0.094g) and DMF (4 ml) were stirred for 30 minutes at 60° C. The reactionmixture was cooled to room temperature and filtered through celite bed.The organic volatiles were evaporated and the residue was acidified withcitric acid. The solid precipitated out was filtered to get pure1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-oneas off white solid (16 mg, 40%). ¹HNMR (400 MHz, DMSO d6): δ 0.84-0.90(m, 3H); 1.66-1.73 (m, 2H); 3.94-3.99 (m, 2H); 4.65 (d, J=5.6 Hz, 2H);6.66 (d, J=9.2 Hz, 1H); 7.55-7.79 (m, 4H); 8.13 (dd, J=8.8 Hz, 2.4 Hz,1H); 8.30 (s, 1H); 8.78 (d, J=2.4 Hz, 1H); 13.56 (s, 1H)

Example 292-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

A mixture of2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(0.2 g, 0.45 mmol) (prepared as given in Example 1), ammonia solution(20 ml) was heated at 125-130° C. in a sealed tube for 5 days. Reactionmixture was cooled to 0° C. and solid was filtered, washed withmethanol, dried and purified by column chromatography using silica gel(100-200 mesh) and 6 to 8% methanol in DCM as an eluent to obtain2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(0.079 g, 41%) as a white solid.

¹HNMR (400 MHz, CD₃OD): δ 1.02 (t, J=7.4 Hz, 3H); 1.72-1.77 (m, 2H);4.02 (t, J=7.8 Hz, 2H); 5.54 (s, 2H); 7.60-7.68 (m, 4H); 8.11 (s, 1H);8.33 (s, 1H).

Example 302-Fluoro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

To a mixture of2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(0.112 g, 0.27 mmol) and tert-butyl nitrite (0.07 ml, 0.54 mmol), 70% HFin pyridine (0.6 ml) was added at 0° C. and stirred for 3 hours at roomtemperature. Reaction mixture was diluted with DCM (10 ml) and washedwith water (10 ml) followed by brine (2×10 ml). Organic layer was driedover Na₂SO₄, concentrated and further purified by preparative HPLC toget pure2-Fluoro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7dihydro-purin-6-one as light brown solid (0.016 g, 2%).

¹HNMR (400 MHz, DMSO d6): δ 0.99 (t, J=7.2 Hz, 3H); 1.74-1.78 (m, 2H);4.06-4.11 (m, 2H); 5.53 (s, 2H); 7.56-7.63 (m, 4H); 8.11 (s, 1H); 8.35(s, 1H)

Example 311-Propyl-2-trifluoromethyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Step 1:2-Iodo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

A mixture of2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(prepared as given in Example 13) (0.169 g, 0.41 mmol), isoamyl nitrite(0.2 ml, 1.5 mmol), iodine (83 mg, 0.32 mmol) was taken in THF (5 ml)and stirred for 2 hours at 80° C. Reaction mixture was cooled andsaturated solution of Na₂S₂O₃ was added and extracted with ethyl acetate(3×5 ml). The organic layer was washed with brine (10 ml), dried overNa₂SO₄ and evaporated to obtain2-Iodo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(93 mg, 44%).

Step 2:1-Propyl-2-trifluoromethyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

A mixture of2-Iodo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(36 mg, 0.068 mmol), Zn dust (10 mg, 0.136 mmol) and THF (2 ml) wasstirred for 2 hours at room temperature. Trifluoromethyl iodide gas waspassed through the reaction mixture and HMPA (2 ml) was added and heatedat 120° C. for 18 hours. The reaction mixture was cooled to roomtemperature, organic volatile solvent was evaporated and the residue wasextracted with DCM (2×10 ml). The organic layer was washed with brine(10 ml), dried over Na₂SO₄, evaporated and purified by preparative HPLCto get1-Propyl-2-trifluoromethyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-oneas pale yellow solid (4.5 mg, 14%).

¹HNMR (400 MHz, DMSO d6): δ 0.93 (t, J=7.6 Hz, 3H); 1.65-1.69 (m, 2H);3.98-4.01 (m, 2H); 5.54 (s, 2H); 7.59-7.63 (m, 2H); 7.68-7.70 (m, 2H);8.18 (s, 1H); 8.58 (s, 1H); 13.95 (s, 1H)

Example 322-Cyclopropyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

A mixture of2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(prepared using same procedure as given in Example 2) (0.1 g, 0.23mmol), Pd(PPh₃)₄ (0.319 g, 0.28 mmol) and cyclopropyl zinc chloridesolution (10 ml, 0.5 M solution) were heated at 100° C. for 30 minutes.Reaction mixture was cooled, diluted with DCM (10 ml). Organic layerwashed with brine (2×10 ml), dried over Na₂SO₄, evaporated and purifiedby preparative TLC to obtain pure2-Cyclopropyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-oneas white solid (23 mg, 23%)

¹HNMR (400 MHz, DMSO d6): δ 1.05 (t, J=7.6 Hz, 3H); 1.11-1.13 (m, 4H);1.81-1.86 (m, 2H); 2.21-2.26 (m, 1H); 4.33 (t, J=7.6 Hz, 2H); 5.51 (s,2H); 7.24-7.42 (m, 2H); 7.49-7.63 (m, 2H); 8.09 (s, 1H); 8.33 (s, 1H)

Example 331-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one

Step 1:1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one

A mixture of2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(0.1 g, 0.239 mmol) and 4-Trifluoromethylphenyl boronic acid (0.038 g,0.239 mmol) in THF (5 ml) were stirred at room temperature under argonand added 1M aqueous NaHCO₃ (0.04 g, 0.478 mmol) and Pd(PPh₃)₄ (0.013 g,0.0119 mmol). The reaction mixture was heated at 80° C. for overnightand the solvent was removed under reduced pressure. The residue waspurified by column chromatography to obtain1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one(0.05 g, 36%) as a white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.65 (t, J=7.2 Hz, 3H); 1.49-1.51 (m, 2H);3.83 (t, J=7.2 Hz, 2H); 5.54 (s, 2H); 7.61-7.71 (m, 4H); 7.83-7.93 (m,4H); 8.19 (s, 1H); 8.61 (s, 1H); 13.62 (bs, 1H).

Examples 34-36 were prepared in an analogous manner of Example 33 fromappropriate intermediates.

Example IUPAC name 341-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one 352-(3-Fluoro-phenyl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 368-(1-Benzyl-1H-pyrazol-4-yl)-2-furan-2-yl-1-propyl-1,7-dihydro-purin-6-one

Example 372-Ethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Step 1:2-Ethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

To a solution of2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(0.1 g, 0.239 mmol) in dioxane (5 ml) under argon was added ethylmagnesium bromide (0.05 g, 1.146 mmol, 1M solution) and 1M zinc chloride(0.031 g, 2.39 mmol, 1M). To this solution Pd(PPh₃)₄ (0.026 g, 0.0239mmol) was added. The reaction mixture was heated at 50° C. forovernight. The reaction mixture was filtered through celite pad and thesolvents were removed under reduced pressure. The residue was purifiedby column chromatography to obtain2-Ethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(0.01 g, 10%) as a white solid.

¹HNMR (400 MHz, DMSO d6): δ 1.03 (t, J=7.2 Hz, 3H); 1.38 (t, J=7.4 Hz,3H); 1.74-1.75 (m, 2H); 2.94-2.96 (m, 2H); 4.12 (t, J=7.2 Hz, 2H); 5.52(s, 2H); 7.57-7.63 (m, 4H); 8.12 (s, 1H); 8.35 (s, 1H)

Examples 38-40 were prepared in an analogous manner of Example 37 fromappropriate intermediates.

Example IUPAC name 381,2-Dipropyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 392-Methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 402-Benzyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Example 418-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one

Step 1:8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one

To a solution of8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one(0.05 g, 0.136 mmol) in THF (5 ml) under argon was added Diisopropylethyl amine (0.05 g, 0.407 mmol) and 1M methyl amine in THF (0.042 g,1.36 mmol). The reaction mixture was heated at 50° C. for overnight. Thereaction mixture concentrated under reduced pressure. The residueobtained was purified by column chromatography to obtain8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one(0.025 g, 51%) as a white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.89 (t, J=7.2 Hz, 3H); 1.52-1.54 (m, 2H);2.83 (s, 3H); 3.89 (t, J=7.2 Hz, 2H); 5.39 (s, 2H); 7.28-7.36 (m, 5H);7.93-8.33 (m, 2H); 12.70 (bs, 1H).

Example 422-Dimethylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Obtained following analogous procedure of Example 41 starting fromappropriate intermediates.

¹HNMR (400 MHz, DMSO d6): δ 0.8 (t, J=7.2 Hz, 3H); 1.58-1.64 (m, 2H);2.74 (s, 6H); 4.02 (t, J=7.2 Hz, 2H); 5.55 (s, 2H); 7.58-7.68 (m, 4H);8.10-8.44 (m, 2H).

Example 438-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one

Step 1:8-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one

To a solution of8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one(0.05 g, 0.136 mmol) in THF (5 ml) under argon was added Diisopropylethyl amine (0.05 g, 0.407 mmol) and 1M dimethyl amine in methanol(0.061 g, 1.36 mmol). The reaction mixture was heated at 50° C. forovernight. The reaction mixture concentrated under reduced pressure. Theresidue obtained was purified by column chromatography to obtain8-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one(0.005 g, 10%) as a white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.86 (t, J=7.2 Hz, 3H); 1.57 (m, 2H); 3.89(m, 2H); 3.93 (s, 3H); 5.39 (s, 2H); 7.27-7.37 (m, 5H); 8.06 (s, 1H);8.36 (s, 1H); 13.23 (bs, 1H).

Example 448-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one

Step 1:8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one

To a solution of8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one(0.05 g, 0.136 mmol) in NMP (1 ml) under argon was added Diisopropylethyl amine (0.035 g, 0.27 mmol) and 4-Trifluoromethyl-benzylamine(0.035 g, 0.203 mmol). The reaction mixture was heated at 110° C. forovernight. The reaction mixture concentrated under reduced pressure. Theresidue was obtained was purified by preparative HPLC to obtain8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one(0.022 g, 32%) as a white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.95 (t, J=7.2 Hz, 3H); 1.63 (m, 2H); 4.00(t, J=7.2 Hz, 2H); 4.65 (s, 2H); 5.36 (s, 2H); 7.27-7.69 (m, 9H); 8.03(s, 1H); 8.31 (s, 1H); 12.6 (bs, 1H).

Examples 45-79 were prepared in an analogous manner of Example 44 fromappropriate intermediates.

Example IUPAC name 458-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-(3-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one 468-(1-Benzyl-1H-pyrazol-4-yl)-2-[2-(4-methoxy-phenyl)-ethylamino]-1-propyl-1,7-dihydro-purin-6-one 478-(1-Benzyl-1H-pyrazol-4-yl)-2-phenethylamino-1-propyl-1,7-dihydro-purin-6-one 488-(1-Benzyl-1H-pyrazol-4-yl)-2-(4-methyl-piperazin-1-yl)-1-propyl-1,7-dihydro-purin-6-one 498-(1-Benzyl-1H-pyrazol-4-yl)-2-piperidin-1-yl-1-propyl-1,7-dihydro-purin-6-one 501-Propyl-2-pyrrolidin-1-yl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 512-Methylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 522-Cyclobutylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 532-Morpholin-4-yl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 542-(2-Hydroxy-ethylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 552-((S)-2-Methoxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 562-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 572-((R)-3-Hydroxy-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 581-Propyl-2-(tetrahydro-pyran-4-ylamino)-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 59(S)-1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic acid amide 60(2R,4R)-4-Hydroxy-1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylicacid 61 2-(2,3-Dihydroxy-propylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 622-(2-Methoxy-ethylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 632-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-ethanesulfonic acid 642-Isobutylamino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one 658-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one 668-(1-Methyl-1H-pyrazol-4-yl)-2-phenethylamino-1-propyl-1,7-dihydro-purin-6-one 67 2-[2-(4-Methoxy-phenyl)-ethylamino]-8-(1-methyl-1H-pyrazol-4-yl)-1- propyl-1,7-dihydro-purin-6-one 681-[8-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-yl]-pyrrolidine-2-carboxylic acid methyl ester 692-Benzylamino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one 702-(4-Methyl-piperazin-1-yl)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one 712-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one 722-Cyclopropylamino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one 738-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-(3-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one 742-(3-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydropurin-6-one 752-(4-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydropurin-6-one 762-(4-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 772-(3-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 782-Morpholin-4-yl-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 792-(2-Hydroxy-ethylamino)-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Example 80{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-aceticacid

Step 1:{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-aceticacid ethyl ester

To a solution of2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(0.1 g, 0.22 mmol) in NMP (1.5 ml) under argon was added triethyl amine(0.113 g, 1.118 mmol) and ethyl glycine hydrochloride (0.096 g, 0.68mmol). The reaction mixture was heated at 100° C. for 16 hours. To thereaction mixture ethyl acetate was added and it was washed with waterand brine. Ethyl acetate layer was dried over sodium sulphate, filteredand concentrated under reduced pressure and residue obtained waspurified by column chromatography to obtain{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-aceticacid ethyl ester (0.080 g, 69%) as an off white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.91 (t, J=7.2 Hz, 3H); 1.2 (t, J=7.2 Hz,3H); 1.52-1.54 (m, 2H); 3.90-4.04 (m, 2H); 4.00-4.16 (m, 4H); 5.52 (s,2H); 7.58-7.74 (m, 4H); 7.98-8.43 (m, 2H); 12.70 (bs, 1H).

Step 2:{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-aceticacid

A mixture of{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-aceticacid ethyl ester in THF (2 ml), MeOH (1 ml) and Water (1 ml) was addedlithium hydroxide (0.02 g, 0.476 mmol) at 0° C. The reaction mixture wasstirred at room temperature for overnight. The reaction mixture wasconcentrated and water was added. It was extracted with ethyl acetate.Ethyl acetate layer was washed with water and brine. Ethyl acetate layerwas dried over sodium sulphate, filtered and concentrated under reducedpressure and the residue obtained was purified by column chromatographyto obtain{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-aceticacid (0.035 g, 46%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ 0.99 (t, J=7.2 Hz, 3H); 1.70-1.80 (m, 2H);4.05 (t, J=7.2 Hz, 2H); 4.12 (s, 2H); 5.48 (s, 2H); 7.54-7.68 (m, 4H);8.04 (s, 1H); 8.26 (s, 1H).

Examples 81-86 were prepared in an analogous manner of Example 80 fromappropriate intermediates.

Example IUPAC name 81[8-(1-Benzyl-1H-pyrazol-4-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-ylamino]-acetic acid ethyl ester 82(Methyl-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-amino)-acetic acid 83(S)-1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2- carboxylic acid84 1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-piperidine-3- carboxylic acid85 (R)-3-Methyl-2-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}- butyric acid86 1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-piperidine-4- carboxylic acid

Example 87 Preparation of2-(3-Fluoro-phenoxy)-8-(1-methyl-4H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one

The first two steps were carried out as described earlier. A mixture of2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one(0.1 g, 0.34 mmol), N-methyl pyrrolidone (2 ml), potassium carbonate(0.093 g, 0.68 mmol) and 3-Fluoro phenol (0.036 ml, 0.4 mmol), wereheated at 85-90° C. for 20 hours. The reaction mixture was cooled to 0°C. and then added water (10 ml). The solid obtained was filtered, washedwith cold water, then washed with diethyl ether, dried to obtain-(3-Fluoro-phenoxy)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one(0.093 g, 75%) as an off white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.96 (t, J=7.2 Hz, 3H); 1.75-1.77 (m, 2H);3.89 (s, 3H); 4.11-4.12 (m, 2H); 7.20-7.25 (m, 2H); 7.33-7.37 (m, 1H);7.50-7.56 (m, 1H); 8.00 (s, 1H); 8.22 (s, 1H); 13.37 (bs, 1H).

Example 88 Preparation of2-(4-methoxy-phenylamino)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one

A mixture of2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one(0.1 g, 0.34 mmol), p-anisidine (0.049 g, 0.4 mmol) and 1-butanol (5ml), were heated at reflux temperature for 20 hours. The reactionmixture was cooled to 20-25° C. and evaporated to dryness, then addedwater (20 ml) to the residue and extracted with ethyl acetate (4×20 ml).The organic layers were mixed and washed with brine (30 ml), dried overNa₂SO₄ and evaporated to dryness and the crude product was washed withdiethyl ether and dried to obtain2-(4-Methoxy-phenylamino)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one(0.0625 g, 48%) as an off white solid.

¹HNMR (400 MHz, CD₃OD): δ 1.04 (t, J=7.2 Hz, 3H); 1.80-1.82 (m, 2H);4.21-4.23 (m, 2H); 4.59 (s, 6H); 6.92 (d, J=8.4 Hz, 2H); 7.38 (d, J=8.8Hz, 2H); 7.96 (s, 1H); 8.09 (s, 1H).

Example 89 Preparation of2-Methoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

To the mixture of methanol (2 ml) and NaH (45 mg, 1.1 mmol),2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(50 mg, 0.11 mmol) was added and refluxed for 2 hours at 80° C. Reactionmixture was cooled, diluted with ethyl acetate (10 ml) and quenched withsaturated NH₄Cl solution. The organic layer was separated and washedwith brine (2×10 ml), dried over Na₂SO₄, filtered and evaporated. Theresidue obtained was purified by preparative HPLC to obtain pure2-Methoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(26 mg, 53%) as an off white solid.

¹HNMR (400 MHz, CD₃OD): δ 0.87-0.96 (m, 3H); 1.68-1.71 (m, 2H);4.02-4.25 (m, 5H); 5.50 (s, 2H); 7.54-7.61 (m, 4H); 8.07 (s, 1H); 8.30(s, 1H)

Examples 90-93 were prepared in an analogous manner of Example 89 fromappropriate intermediates.

Example IUPAC name 902-Cyclopentyloxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 91{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-acetic acid ethyl ester 921-Propyl-2-(2,2,2-trifluoro-ethoxy)-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one 932-(2-Methoxy-ethoxy)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Example 94 Preparation of6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylicacid amide

Step 1:6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile

A mixture of2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(4.0 g, 9.16 mmol), NaCN (0.67 g, 13.74 mmol), NaI (2.0 g, 9.16 mmol)and DMF (30 ml) were stirred for 48 hrs at 60° C. Reaction mixture wascooled to 20-25° C. and water was added and solid filtered off. Thecrude product was purified by column chromatography using silica gel(100-200 mesh) and 2 to 4% methanol in DCM as an eluent to obtain6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile(2.6 g, 67%) as an off white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.92 (t, J=7.2 Hz, 3H); 1.71-1.77 (m, 2H);4.12 (t, J=7.6 Hz, 2H); 5.51 (s, 2H); 7.57-7.67 (m, 4H); 8.14 (s, 1H);8.55 (s, 1H); 14.01 (bs, 1H)

Step 2:6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylicacid amide

A mixture of6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile(40 mg, 0.0934 mmol), NaOH (6 mg, 0.140 mmol) and Ethanol:water (3:1) (2ml) were stirred at 50° C. for 18 hours. Reaction mixture was cooled andorganic volatiles were evaporated and the residue obtained was dissolvedin DCM (10 ml) and washed with brine (10 ml). Organic layer was driedover Na₂SO₄ and evaporated to obtain pure6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylicacid amide (32 mg, 78%) as an off white solid.

¹HNMR (400 MHz, CD₃OD): δ 0.96 (t, J=7.6 Hz, 3H); 1.78-1.84 (m, 2H);4.22 (t, J=8 Hz, 2H); 5.51 (s, 2H); 7.55-7.61 (m, 4H); 8.13 (s, 1H);8.34 (s, 1H).

Example 958-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carbonitrile

Obtained following analogous procedure of Example 94 starting fromappropriate intermediates.

¹HNMR (400 MHz, CD₃OD): 1.03 (t, J=7.6 Hz, 3H); 1.85-1.87 (m, 2H); 4.28(t, J=7.6 Hz, 2H); 5.52 (s, 2H); 7.22-7.24 (m, 2H); 7.65-7.69 (m, 1H);8.14 (s, 1H); 8.39 (s, 1H).

Example 968-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carboxylicacid

A mixture of8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carbonitrile (65 mg, 0.145 mmol), NaOH (11mg, 0.290 mmol) and Ethanol:water (3:1) (6 ml) were stirred at 55-60° C.for 2 hours. Reaction mixture was cooled and organic volatiles wereevaporated and to the residue water (2 ml) was added and acidified by 2NHCl upto pH (1-2), solid filtered off. The crude product was purified bypreparative HPLC to obtain pure8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carboxylicacid (21 mg, 31%) as a white solid.

¹HNMR (400 MHz, CD₃OD): δ 0.98 (t, J=9.2 Hz, 3H); 1.68-1.74 (m, 2H);3.99 (t, J=7.2 Hz, 2H); 5.50 (s, 2H); 7.54-7.61 (m, 4H); 8.07 (s, 1H);8.28 (s, 1H).

Example 977-Methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Step 1:2-Chloro-7-methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

A mixture of2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(200 mg, 0.46 mmol), K₂CO₃ (95 mg, 0.69 mmol), MeI (85 mg, 0.60 mmol)and DMF (2 ml) were stirred at 60° C. for 2 hours. Reaction mixture wascooled, diluted with water (10 ml) and extracted with ethyl acetate (2×5ml). The organic layer was washed with brine (2×10 ml), dried overNa₂SO₄ and evaporated to obtain2-Chloro-7-methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one(120 mg, 58%)

¹HNMR (4001\4 Hz, DMSO d6): δ 0.91-0.95 (m, 3H); 1.66-1.71 (m, 2H); 4.12(s, 3H); 4.15-4.18 (m, 2H); 5.55 (s, 2H); 7.62-7.63 (m, 2H); 7.69-7.72(m, 2H); 8.12 (s, 1H); 8.68 (s, 1H)

Step 2: Preparation of7-Methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Step-2 was carried out as described in Step-5 of Example 28

¹HNMR (400 MHz, CD₃OD): δ 0.87 (t, J=7.6 Hz, 3H); 1.66-1.71 (m, 2H);3.84 (s, 3H); 3.97 (t, J=7.6 Hz, 2H); 5.56 (s, 2H); 7.61-7.63 (m, 2H);7.69-7.71 (m, 2H); 8.11 (s, 1H); 8.39 (s, 1H); 8.66 (s, 1H)

Example 982-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-7-methyl-1-propyl-1,7-dihydro-purin-6-one

Obtained following analogous procedure of Example 97 starting fromappropriate intermediates.

¹HNMR (400 MHz, DMSO d6): δ 0.94 (t, J=7.2 Hz, 3H); 1.71-1.74 (m, 2H);4.14-4.20 (m, 5H); 5.59 (s, 2H); 7.31 (d, J=7.6 Hz, 1H); 7.45 (d, J=12Hz, 1H); 7.82 (dd, J=7.6 Hz, 1H); 8.15 (d, J=6 Hz, 1H); 8.69 (d, J=13.6Hz, 1H);

Example 99 Preparation of{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-aceticacid

A mixture of{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-aceticacid ethyl ester (56 mg, 0.11 mmol), LiOH:6H₂O (14 mg, 0.33 mmol) andTHF:MeOH:Water (3:2:1) (1 ml) were stirred for 3 hours at ambienttemperature. Organic volatiles were evaporated and the residue wasacidified with 1N HCl to obtain{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-aceticacid as an off white solid (20 mg, 38%)

¹HNMR (400 MHz, CD₃OD): δ 0.99 (t, J=7.6 Hz, 3H); 1.77-1.82 (m, 2H);4.13 (t, J=7.6 Hz, 2H); 5.03 (s, 2H); 5.54 (s, 2H); 7.59-7.67 (m, 4H);8.12 (s, 1H); 8.36 (s, 1H)

Example 100 Preparation of2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

A mixture of1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione(100 mg, 0.24 mmol), Sodium chloro difluoroacetate (47 mg, 0.31 mmol),Cs₂CO₃ (117 mg, 0.36 mmol) and DMF (2 ml) were stirred at 60° C. for 18hours. Reaction mixture was cooled and diluted with water (10 ml), solidmaterials were filtered off and it was purified by preparative HPLC toobtain2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-oneas off white solid (11 mg, 10%) and

¹HNMR (400 MHz, DMSO d6): δ 0.86 (t, J=7.6 Hz, 3H); 1.53-1.58 (m, 2H);3.79 (t, J=7.6 Hz, 2H); 5.56 (s, 21-1); 7.60-7.61 (m, 2H); 7.68-7.70 (m,2H); 7.99 (s, 1H); 8.16 (t, J=55.8 Hz, 1H); 8.6 (s, 1H); 12.22 (bs, 1H)

3-Difluoromethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione

¹HNMR (400 MHz, DMSO d6): δ 0.87 (t, J=7.6 Hz, 3H); 1.53-1.58 (m, 2H);3.79-3.83 (m, 2H); 5.55 (s, 2H); 7.60-7.71 (m, 4H); 7.80 (t, J=55.6.8Hz, 1H); 7.90 (s, 1H); 8.46 (s, 1H); 12.44 (bs, 1H)

Example 101 Preparation of1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one

Step 1:8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

Step-1 was carried out as described in Step-5 of Example 28

Step 2:1-Propyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

Step-2 was carried out as described in Step-3 of Example 27

Step 3:1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one

A mixture of1-Propyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(100 mg, 0.2 mmol), 3-Bromomethylpyridine (55 mg, 0.3 mmol), K₂CO₃ (50mg, 0.3 mmol) and DMF were stirred at 60° C. for 2 hours. Organicvolatiles were evaporated and purified to obtain pure1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one(8 mg, 6%) as an colourless oil.

Step 4:1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one

Step-4 was carried out as described in Step-5 of Example 15

¹HNMR (400 MHz, DMSO d6): δ 0.99 (t, J=7.6 Hz, 3H); 1.80-1.86 (m, 2H);4.10 (t, J=7.2 Hz, 2H); 5.81 (s, 2H); 8.11-8.14 (dd, J=8.8 Hz, 4.2 Hz,1H); 8.26 (s, 1H); 8.46 (s, 1H); 8.63 (d, J=8.4 Hz, 1H); 8.73 (s, 1H);8.88 (d, J=4.8 Hz, 1H); 8.98 (s, 1H)

Example 1021-Propyl-8-[1-(6-trifluoromethyl-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one

Obtained following analogous procedure of Example 101 starting fromappropriate intermediates.

¹HNMR (400 MHz, DMSO d6): δ 0.87 (t, J=7.6 Hz, 3H); 1.66-1.71 (m, 2H);3.96 (t, J=7.6 Hz, 2H); 5.63 (s, 2H); 7.91-7.94 (m, 2H); 8.20 (s, 1H);8.36 (s, 1H); 8.60 (s, 1H); 8.75 (s, 1H)

Example 103 Preparation of8-{1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one

Step 1:1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid ethyl ester

A mixture of 1H-Pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.713mmol), potassium carbonate (0.019 g, 1.42 mmol), Methanesulfonic acid1-(2,4-difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester (0.32 g, 1.07mmol) were taken in DMF (2 ml). The reaction mixture was heated at55-60° C. for 20 hour. The mixture was cooled to room temperature andthen to this reaction mixture water (20 ml) was added and extracted withethyl acetate (3×25 ml), organic layers were combined and washed withbrine (25 ml), dried over Na₂SO₄ and evaporated to dryness to obtain1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.22 g, 91%) as a brownish sticky mass.

¹HNMR (400 MHz, CDCl₃): δ 1.36 (t, J=6.8 Hz, 3H); 2.39 (dd, J=6.0, 17.2Hz, 1H); 2.78 (dd, J=8.8, 17.2 Hz, 1H); 3.17-3.22 (m, 1H); 3.62 (dd,J=4.8, 10.0 Hz, 1H); 3.86 (dd, J=7.6, 10.0 Hz, 1H); 4.27-4.34 (m, 4H);6.90-6.94 (m, 2H); 7.32-7.38 (m, 1H); 7.94 (s, 1H); 8.04 (s, 1H).

Step 2:1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid

1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.222 g, 0.62 mmol) was dissolved in a mixture ofsolvents Methanol:water (3:1, 5 ml) and KOH (0.07 g, 125 mmol) was addedto the reaction mixture and then stirred at 50-55° C. for 3 hours.Solvents were removed and the residue was diluted with water (3 ml) andwashed with DCM (3×10 ml) and acidified with dil. HCl. It was extractedwith ethyl acetate (3×15 ml), organic layers were mixed and washed withbrine (20 ml), dried over Na₂SO₄ and evaporated to dryness to obtain1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid (0.18 g, 90%) as a brownish sticky mass.

¹HNMR (400 MHz, CDCl₃): δ 2.42 (dd, J=4.4, 17.6 Hz, 1H); 2.80 (dd,J=8.8, 17.6 Hz, 1H); 3.17-3.25 (m, 1H); 3.63-3.67 (m, 1H); 3.87-3.91 (m,1H); 4.32-4.34 (m, 2H); 6.91-6.96 (m, 2H); 7.34-7.38 (m, 1H); 8.01 (s,1H); 8.04 (s, 1H).

Step 3:1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide

A mixture of 5,6-Diamino-3-propyl-1H-pyrimidine-2,4-dione (0.12 g, 0.67mmol) and1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid (0.18 g, 0.56 mmol) in methanol (6 ml) was cooled to 0° C. andadded EDCI.HCl (0.15 g, 0.78 mmol) and stirred at 25° C. for 20 hours.Solvents were removed under reduced pressure and to this reactionmixture water (10 ml) was added. Solid obtained was filtered off andwashed with cold water (20 ml) followed by diethyl ether (25 ml). It wasthen dried and the crude product was purified by column chromatographyusing silica gel (100-200 mesh) and 6% methanol in DCM as an eluent toobtain1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide(0.165 g, 60%) as an off white solid.

¹HNMR (400 MHz, DMSO d6): δ 0.82 (t, J=7.2 Hz, 3H); 1.46-1.51 (m, 2H);2.31 (dd, J=6.4, 16.8 Hz, 1H); 2.58 (dd, J=8.8, 16.8 Hz, 1H); 3.02-3.04(m, 1H); 3.55 (dd, J=5.6, 9.6 Hz, 1H); 3.64 (t, J=8.0 Hz, 2H); 3.78 (t,J=8.0 Hz, 1H); 4.31 (d, J=7.2 Hz, 2H); 5.99 (s, 2H); 7.12-7.17 (m, 1H);7.33-7.39 (m, 1H); 7.44-7.48 (m, 1H); 7.98 (s, 1H); 8.30 (s, 1H); 8.53(s, 1H); 10.42 (s, 1H).

Step 4:2-Chloro-8-{1-[1-(2,4-difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one

A mixture of1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide(0.165 g, 0.338 mmol), phenyl phosphoric dichloride (5 ml) were heatedat 125-130° C. for 30 hours. Reaction mixture was cooled to 20-25° C.and then solvents were removed under reduced pressure and residue waswashed with diethyl ether. The crude product was purified by columnchromatography using silica gel (100-200 mesh) and 4-5% methanol in DCMas an eluent to obtain2-Chloro-8-{1-[1-(2,4-difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one(0.04 g, 24%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ 0.92 (t, J=7.2 Hz, 3H); 1.69-1.73 (m, 2H);2.39-2.45 (m, 1H); 2.62-2.68 (m, 1H); 3.10-3.14 (m, 1H); 3.60-3.65 (m,1H); 3.80-3.85 (m, 1H); 4.34 (t, J=7.2 Hz, 2H); 4.46-4.48 (m, 2H);6.89-6.83 (m, 1H); 6.96-7.01 (m, 1H); 7.29-7.33 (m, 1H); 8.13 (s, 1H);8.36 (s, 1H).

Step 5:8-{1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one

A mixture of2-Chloro-8-{1-[1-(2,4-difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1,1-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one(25.0 mg, 0.051 mmol), Pd/C (10%) (5.0 mg), DMF (1 ml) and H₂O (0.25 ml)and ammonium formate (64 mg, 1.02 mmol) were heated at 85-90° C. for 1hour. Reaction mixture was cooled to 20-25° C. and then it was filteredthrough celite bed, washed with methanol (10 ml). Solvents were removedunder reduced pressure and to this residue water (1 ml) was added andacidified with citric acid to get pH (1-2). Solid obtained was filteredoff and washed with cold water, followed by diethyl ether. Solid crudeproduct was purified by column chromatography using preparative TLC toobtain8-{1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one(5.5 mg, 33%) as a pale yellow solid.

¹HNMR (400 MHz, CD₃OD): δ 1.00 (t, J=7.2 Hz, 3H); 1.80-1.86 (m, 2H);2.52 (dd, J=6.4, 17.2 Hz, 1H); 2.76 (dd, J=8.8, 17.2 Hz, 1H); 3.18-3.23(m, 1H); 3.72 (dd, J=5.6, 10.0 Hz, 1H); 3.93 (dd, J=8.0, 10.0 Hz, 1H);4.08 (t, J=7.6 Hz, 2H); 4.44 (d, J=7.2 Hz, 2H); 7.00-7.04 (m, 1H);7.07-7.13 (m, 1H); 7.40-7.46 (m, 1H); 8.13 (s, 1H); 8.26 (s, 1H); 8.34(s, 1H).

Biological Activity Radioligand Binding for A_(2B) Adenosine Receptor

Human A_(2B) adenosine receptor cDNA was stably transfected into HEK-293cells. HEK-A2B cells were harvested by trypsinization with 0.25%Trypsin-EDTA (Sigma), and washed in 1×PBS at 1500 rpm for 5 minutes atroom temperature. The cells were washed twice in wash buffer containing150 mM NaCl, 1 mM EDTA, 50 mM Tris (pH-7.4) at 1500 rpm for 10 minutesat room temperature and incubated for 10 mM at 4° C. in sonicationbuffer containing 1 mM EDTA, 5 mM Tris (pH 7.4). The cells weresonicated on ice for 6 min with six intermittent pulses of 9 second eachand centrifuged at 1000×g for 10 minutes at 4° C. The pellet wasdiscarded and the supernatant was centrifuged at 49,000×g for 45 minutesat 4° C. The protein pellet was resuspended in buffer containing 1 mMEDTA, 5 mM Tris (pH-7.4), 1 Unit/ml adenosine deaminase (ADA) andincubated for 30 minutes at room temperature. The lysate was washedtwice with buffer containing 1 mM EDTA, 5 mM Tris (pH-7.4) at 49,000×gfor 45 minutes at 4° C. and the protein pellet was resuspended in 50 mMTris, pH-7.4 supplemented with 1 Unit/ml ADA and 10% sucrose. Frozenaliquots were stored at −80° C.

Competition assays were started by mixing 1.6 nM [³H]-MRS-1754 withvarious concentrations of test compounds and 10 μg membrane protein inReaction buffer (50 mM Tris pH 6.5, 5 mM MgCl₂, 1 mM EDTA) supplementedwith 1 U/ml Adenosine deaminase. The assay reactions were incubated for90 minutes at room temperature and stopped by filtration using 96well-plate harvester (Molecular Devices) and washed four times with icecold 50 mM Tris (pH 7.4). Non specific binding was determined inpresence of 200 μM NECA. Radioligand binding was read at Liquidscintillation counter (Perkin Elmer) and the affinities of compounds(i.e. K_(i) values) were calculated using GraphPad software.

Compounds tested had micromolar to nanomolar activity.

Radioligand Binding for A₁ Adenosine Receptor

Human A₁ adenosine receptor cDNA was stably transfected into HEK-293cells. HEK-A₁ cells were harvested by trypsinization with 0.25%Trypsin-EDTA (Sigma), and washed in 1×PBS at 1500 rpm for 5 minutes atroom temperature. The cells were washed twice in wash buffer containing150 mM NaCl, 1 mM EDTA, 50 mM Tris (pH-7.4) at 1500 rpm for 10 minutesat room temperature and incubated for 10 min at 4° C. in sonicationbuffer containing 1 mM EDTA, 5 mM Tris (pH 7.4). The cells weresonicated on ice for 6 min with six intermittent pulses of 9 secondseach and centrifuged at 1000×g for 10 minutes at 4° C. The pellet wasdiscarded and the supernatant was centrifuged at 49,000×g for 45 minutesat 4° C. The protein pellet was resuspended in buffer containing 1 mMEDTA, 5 mM Tris (pH-7.4), 1 Unit/ml adenosine deaminase (ADA) andincubated for 30 minutes at room temperature. The lysate was washedtwice with buffer containing 1 mM EDTA, 5 mM Tris (pH-7.4) at 49,000×gfor 45 minutes at 4° C. and the protein pellet was resuspended in 50 mMTris, (pH-7.4) supplemented with 1 Unit/ml ADA and 10% sucrose. Frozenaliquots were stored at −80° C.

Competition assays were started by mixing 1 nM [³H]-DPCPX with variousconcentrations of test compounds and 5 μg membrane protein in Reactionbuffer (50 mM Tris pH 7.4, 1 mM EDTA) supplemented with 1 Unit/ml ADA.The assay reactions were incubated for 90 minutes at room temperatureand stopped by filtration using 96 well-plate harvester (MolecularDevices) and washed four times with ice cold 50 mM Tris (pH 7.4). Nonspecific binding was determined in presence of 200 μM NECA. Radioligandbinding was read at Liquid scintillation counter (Perkin Elmer) and theaffinities of compounds (i.e. K_(i) values) were calculated usingGraphPad software.

Compounds tested had micromolar to nanomolar activity.

Radioligand Binding for A₂ Adenosine Receptor

Human A_(2A) adenosine receptor cDNA was stably transfected into HEK-293cells. HEK-A_(2A) cells were harvested by trypsinization with 0.25%Trypsin-EDTA (Sigma), and washed in 1×PBS at 1500 rpm for 5 minutes atroom temperature. The cells were washed twice in wash buffer containing150 mM NaCl, 1 mM EDTA, 50 mM Tris (pH-7.4) at 1500 rpm for 10 minutesat room temperature and incubated for 10 min at 4° C. in sonicationbuffer containing 1 mM EDTA, 5 mM (Tris pH 7.4). The cells weresonicated on ice for 6 min with six intermittent pulses of 9 second eachand centrifuged at 1000×g for 10 minutes at 4° C. The pellet wasdiscarded and the supernatant was centrifuged at 49,000×g for 45 minutesat 4° C. The protein pellet was resuspended in buffer containing 1 mMEDTA, 5 mM Tris (pH-7.4) supplemented with 1 Unit/ml adenosine deaminase(ADA) and incubated for 30 minutes at room temperature. The lysate waswashed twice with buffer containing 1 mM EDTA, 5 mM Tris (pH-7.4) at49,000×g for 45 minutes at 4° C. and the protein pellet was resuspendedin 50 mM Tris, pH-7.4 supplemented with 1 Unit/ml ADA and 10% sucrose.Frozen aliquots were stored at −80° C.

Competition assays were started by mixing 2 nM [³H]-ZM-241385 withvarious concentrations of test compounds and 5 μg membrane protein inReaction buffer (50 mM Tris pH 7.4, 1 mM EDTA) supplemented with 1Unit/ml ADA. The assay reactions were incubated for 90 minutes at roomtemperature and stopped by filtration using 96 well-plate harvester(Molecular Devices) and washed four times with ice cold 50 mM Tris (pH7.4). Non specific binding was determined in presence of 200 μM NECA.Radioligand binding was read at Liquid scintillation counter (PerkinElmer) and the affinities of compounds (i.e. K_(i) values) werecalculated using GraphPad software.

Compounds tested had micromolar to nanomolar activity.

Radioligand Binding for A₃ Adenosine Receptor

Human A₃ adenosine receptor cDNA was stably transfected into HEK-293cells. HEK-A₃ cells were harvested by trypsinization with 0.25%Trypsin-EDTA (Sigma), and washed in 1×PBS at 1500 rpm for 5 minutes atroom temperature. The cells were washed twice in wash buffer containing10 mM EDTA, 10 mM HEPES (pH-7.4) at 1500 rpm for 10 minutes at roomtemperature and incubated for 10 min at 4° C. in sonication buffercontaining 1 mM EDTA, 10 mM HEPES (pH 7.4). The cells were sonicated onice for 6 min with six intermittent pulses of 9 seconds each andcentrifuged at 1000×g for 10 minutes at 4° C. The pellet was discardedand the supernatant was centrifuged at 49,000×g for 45 minutes at 4° C.The protein pellet was resuspended in buffer containing 1 mM EDTA, 10 mMHEPES (pH 7.4) supplemented with 1 Unit/ml adenosine deaminase (ADA) andincubated for 30 minutes at room temperature. The lysate was washedtwice with buffer containing 1 mM EDTA, 10 mM HEPES (pH-7.4) at 49,000×gfor 45 minutes at 4° C. and the protein pellet was resuspended in buffercontaining 1 mM EDTA, 5 mM Tris (pH-7.4) supplemented with 1 Unit/ml ADAand 10% sucrose. Frozen aliquots were stored at −80° C.

Competition assays were started by mixing 2 nM [3H]-HEM-ADO with variousconcentrations of test compounds and 5 μg membrane protein in Reactionbuffer (50 mM Tris pH 7.4, 1 mM EDTA, 10 mM MgCl₂) supplemented with 1Unit/ml ADA. The assay reactions were incubated for 90 minutes at roomtemperature and stopped by filtration using 96 well-plate harvester(Molecular Devices) and washed four times with ice cold 50 mM Tris pH7.4. Non specific binding was determined in presence of 200 μM NECA.Radioligand binding was read at Liquid scintillation counter (PerkinElmer) and the affinities of compounds (i.e. K_(i) values) werecalculated using GraphPad software.

Compounds tested had micromolar to nanomolar activity.

Although the subject matter has been described in considerable detailwith reference to certain preferred embodiments thereof, otherembodiments are possible. As such, the spirit and scope of the appendedclaims should be limited to the description of the preferred embodimentcontained therein.

1. A compound of formula I

or its tautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein Y is selected from Nand CR; R is selected from H, hydroxy, alkoxy, alkyl, and aryl; R¹ isselected from a group consisting of alkyl, alkenyl and alkynyl, whereinone or more methylene groups are optionally replaced by hetero atoms orgroups selected from —O—, —S(O)p-, —N(R^(a))—, or —C(O) provided thatthe heteroatom is not adjacent to N in the ring; p is 0, 1 or 2; whereinalkyl, alkenyl and alkynyl are unsubstituted or substitutedindependently with alkoxy, acyl, acylamino, acyloxy, amino,monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy, carboxyalkyl, —SO₃H, aminocarbonylamino,hydroxyamino, alkoxyamino, nitro, —S(O)₂NR^(a)R^(a), —NR^(a)S(O)₂R^(a),or —S(O)_(p)R^(a); R² is selected from a group consisting of hydrogen,halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl,alkynyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy, alkoxy,—NR^(b)R^(b), —S(O)_(p)R^(b), cycloalkyl, cycloalkylalkyl,cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl,heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl andheteroaryloxy; wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl,cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl,heteroarylalkyl, heteroaryloxy and R^(b) are unsubstituted orsubstituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl,acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino,hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen,hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,carboxyalkyl, —SO₃H, arylamino, cycloalkylamino, heteroarylamino,heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl,cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclyloxy, —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl,haloalkoxy, amino, substituted amino, cyano and —S(O)_(p)R^(d); R³ isselected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryland heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl are unsubstituted or substituted independently withalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino,cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,alkylcarboxyalkyloxy, —SO₃H, aryl, aryloxy, cycloalkyloxy, heteroaryl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy,hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxyd, alkoxy, halogen, haloalkyl,haloalkoxy, amino, substituted amino, cyano and —S(O)_(p)R^(d); X isoptionally substituted arylene or optionally substituted heteroarylene;A is selected from a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene and(C₂-C₆)alkynylene group, wherein 1 to 4 methylene groups are optionallyreplaced by groups independently selected from O, —S(O)_(p)—,—N(R^(b))—, and —C(O)—; wherein alkylene, alkenylene, and alkynylene areunsubstituted or substituted independently with alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,monoalkylamino, dialkylamino, arylamino, cycloalkylamino,heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,alkylcarboxyalkyloxy —SO₃H, aryl, aryloxy, cycloalkyloxy, heteroaryl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy,hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano and —S(O)_(p)R^(d); B is selected fromhydrogen, heterocyclyl, cycloalkyl, aryl and heteroaryl; whereinheterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted orsubstituted independently with alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, aryloxy,amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino,heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,alkylcarboxyalkyloxy —SO₃H, aryl, arylalkyl, aryloxy, cycloalkyloxy,heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino,alkoxyamino, nitro, S(O)₂NR^(b)R^(b), —NR^(b)S(O)₂R^(b) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl,halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and—S(O)_(p)R^(d); R^(a) is independently selected from the groupconsisting of hydrogen and alkyl; R^(b) is independently selected fromthe group consisting of hydrogen, alkyl, acyl, carboxyalkyl,carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylheteroarylalkyl, heterocyclyl and heterocyclylalkyl; R^(c) is selectedfrom hydrogen, alkyl, aryl, heteroaryl and heterocyclyl; R^(d) isselected from alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; andp is 0, 1 or
 2. 2. A compound of formula (I) as claimed in claim 1 orits tautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein Y is N; R¹ isselected from a group consisting of alkyl, alkenyl and alkynyl, whereinalkyl, alkenyl and alkynyl are unsubstituted or substitutedindependently with alkoxy, acyl, acylamino, acyloxy, amino,monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, haloalkyl, hydroxyl, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy or carboxyalkyl; R² is selected from a groupconsisting of hydrogen, halogen, cyano, nitro, carboxy, acyl,aminocarbonyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxyalkyl,haloalkyl, haloalkyloxy, alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b),cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl,heteroarylalkyl and heteroaryloxy; wherein alkyl, alkenyl, alkynyl,alkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl,arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,heteroaryl, heteroarylalkyl, heteroaryloxy and R^(b) are unsubstitutedor substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl,acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino,hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen,hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,carboxyalkyl, —SO₃H, arylamino, cycloalkylamino, heteroarylamino,heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl,cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclyloxy, —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, haloalkyl,haloalkoxy, amino, substituted amino, cyano or —S(O)_(p)R^(d); R³ isselected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryland heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl are unsubstituted or substituted independently withalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino,cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl,keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl,carboxyalkyloxy, alkylcarboxyalkyloxy, —SO₃H, aryl, aryloxy,cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro,S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d); wherein eachsubstituent is unsubstituted or substituted with 1, 2, or 3 substituentsindependently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxyd, alkoxy, halogen, CF₃, amino, substituted amino, cyano or—S(O)_(p)R^(d); X is either an optionally substituted arylene or anoptionally substituted heteroarylene; A is selected from a bond,(C₁-C₆)alkylene, (C₂-C₆)alkenylene or (C₂-C₆)alkynylene group, wherein 1to 4 methylene groups are optionally replaced by groups independentlyselected from O, —S(O)_(p)—, —N(R^(b))—, or —C(O)—; wherein alkylene,alkenylene, and alkynylene are unsubstituted or substitutedindependently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino,dialkylamino, arylamino, cycloalkylamino, heteroarylamino,heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy,alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino,nitro, S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or —S(O)_(p)R^(d); whereineach substituent is unsubstituted or substituted with 1, 2, or 3substituents independently selected from alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxyl, alkoxy, halogen, CF₃, amino, substituted amino,cyano or —S(O)_(p)R^(d); B is selected from hydrogen, heterocyclyl,cycloalkyl, aryl or heteroaryl; wherein heterocyclyl, cycloalkyl, aryland heteroaryl are unsubstituted or substituted independently withalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino,dialkylamino, arylamino, cycloalkylamino, heteroarylamino,heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy,alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(b)R^(b),—NR^(b)S(O)₂R^(b) or —S(O)_(p)R^(d); wherein each substituent isunsubstituted or substituted with 1, 2, or 3 substituents independentlyselected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy,amino, substituted amino, cyano or —S(O)_(p)R^(d); R^(a) isindependently selected from the group consisting of hydrogen and alkyl;R^(b) is independently selected from the group consisting of hydrogen,alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl andheterocyclylalkyl; R^(c) is selected from hydrogen, alkyl, aryl,heteroaryl or heterocyclyl; R^(d) is selected from alkyl, cycloalkyl,aryl, heterocyclyl or heteroaryl; and p is 0, 1 or
 2. 3. A compound offormula (I) as claimed in claim 1 or its tautomers, polymorphs,stereoisomers, prodrugs, solvate or a pharmaceutically acceptable saltsthereof, wherein Y is CR; R is selected from H, hydroxy, alkoxy, alkyl,or aryl; R¹ is selected from a group consisting of alkyl, alkenyl andalkynyl, wherein alkyl, alkenyl and alkynyl are unsubstituted orsubstituted independently with alkoxy, acyl, acylamino, acyloxy, amino,monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy or carboxyalkyl; R² is selected from a groupconsisting of hydrogen, halogen, cyano, nitro, carboxy, acyl,aminocarbonyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl,haloalkyloxy, alkoxy, and —NR^(b)R^(b); wherein alkyl, alkenyl, alkynyl,alkoxy and R^(b) are unsubstituted or substituted independently withalkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino,monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino,aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO₃H, arylamino,cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl,alkoxycarbonylamino, cycloalkyl or cycloalkenyl; R³ is selected from agroup consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; X iseither an optionally substituted arylene or an optionally substitutedheteroarylene; A is selected from a bond, (C₁-C₆)alkylene,(C₂-C₆)alkenylene or (C₂-C₆)alkynylene group, wherein 1 to 4 methylenegroups are optionally replaced by groups, independently selected from O,—S(O)_(P)—, —N(R^(b))—, or —C(O)—; B is selected from hydrogen,heterocyclyl, cycloalkyl, aryl or heteroaryl; wherein heterocyclyl,cycloalkyl, aryl and heteroaryl are unsubstituted or substitutedindependently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,monoalkylamino, dialkylamino, arylamino, cycloalkylamino,heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,alkylcarboxyalkyloxy —SO₃H, aryl, arylalkyl, aryloxy, cycloalkyloxy,heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino,alkoxyamino, nitro, S(O)₂NR^(b)R^(b), —NR^(b)S(O)₂R^(b) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl,halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or—S(O)_(p)R^(d); R^(b) is independently selected from the groupconsisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylheteroarylalkyl, heterocyclyl and heterocyclylalkyl; R^(d) is selectedfrom alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and p is 0, 1or
 2. 4. A compound of formula (I) as claimed in claim 1 or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein Y is N or CR; R isselected from H, hydroxy, alkoxy, alkyl, or aryl; R¹ is selected from agroup consisting of alkyl, alkenyl and alkynyl; R² is selected from agroup consisting of hydrogen, halogen, cyano, nitro, carboxy, acyl,alkyl, alkenyl, alkynyl, alkoxy, —NR^(b)R^(b), cycloalkyl, cycloalkyoxy,aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl andheteroaryloxy; wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkyoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl,heteroaryloxy and R^(b) are unsubstituted or substituted independentlywith alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro,amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino,aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO₃H, arylamino,cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl,alkoxycarbonylamino, cycloalkyl or cycloalkenyl; R³ is selected from agroup consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl andheteroarylalkyl; X is an optionally substituted phenyl; A is selectedfrom a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or (C₂-C₆)alkynylenegroup wherein 1 to 4 methylene groups are optionally replaced by groupsindependently selected from O, —S(O)_(p)—, —N(R^(b))—, or —C(O)—; B isselected from hydrogen, heterocyclyl, cycloalkyl, aryl or heteroaryl;wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstitutedor substituted independently with alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino,heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,alkylcarboxyalkyloxy —SO₃H, aryl, arylalkyl, aryloxy, cycloalkyloxy,heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino,alkoxyamino, nitro, S(O)₂NR^(b)R^(b), —NR^(b)S(O)₂R^(b) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl,halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or—S(O)_(p)R^(d); R^(b) is independently selected from the groupconsisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylheteroarylalkyl, heterocyclyl and heterocyclylalkyl; R^(d) is selectedfrom alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and p is 0, 1or
 2. 5. A compound of formula (I) as claimed in claim 1 or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein Y is selected from Nor CR; R is selected from H, hydroxyl, alkoxy, alkyl, or aryl; R¹ isselected from a group consisting of alkyl, alkenyl and alkynyl; whereinalkyl, alkenyl and alkynyl are unsubstituted or substitutedindependently with alkoxy, acyl, acylamino, acyloxy, amino,monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, haloalkyl, hydroxyl, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy, carboxyalkyl, —SO₃H, aminocarbonylamino,hydroxyamino, alkoxyamino or nitro; R² is selected from a groupconsisting of hydrogen, halogen, cyano, nitro, carboxy, acyl,aminocarbonyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxyalkyl,haloalkyl, haloalkyloxy, alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b),cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy; whereinalkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl,heterocyclyloxy, heteroaryl and heteroaryloxy and R^(b) areunsubstituted or substituted independently with alkyl, alkenyl, alkynyl,alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino,dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido,cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy,alkylcarboxy, carboxyalkyl, —SO₃H, arylamino, cycloalkylamino,heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,cycloalkyl, cycloalkyloxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy,heteroaryl, heteroaryloxy, —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, haloalkyl,haloalkoxy, amino, substituted amino, cyano or —S(O)_(p)R^(d); R³ isselected from a group consisting of hydrogen, alkyl, alkenyl andalkynyl; wherein alkyl, alkenyl and alkynyl are unsubstituted orsubstituted independently with alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, acyl, acylamino, acyloxy, amino, monoalkylamino,dialkylamino, arylamino, cycloalkylamino, heteroarylamino,heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy,alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy,—SO₃H, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyaminoor nitro; X is an optionally substituted heteroarylene; A is selectedfrom a bond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or (C₂-C₆)alkynylenegroup, wherein 1 to 4 methylene groups are optionally replaced by groupsindependently selected from O, —S(O)_(p)—, —N(R^(b))—, or —C(O)—;wherein alkylene, alkenylene, and alkynylene are unsubstituted orsubstituted independently with alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, acyl, acylamino, acyloxy, amino, monoalkylamino,dialkylamino, arylamino, cycloalkylamino, heteroarylamino,heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy,alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H,aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyaminoor nitro; B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl orheteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl areunsubstituted or substituted independently with alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino,acyloxy, amino, monoalkylamino, dialkylamino, arylamino,cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl,keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl,carboxyalkyloxy, alkylcarboxyalkyloxy —SO₃H, aryl, arylalkyl, aryloxy,cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,hydroxyamino, alkoxyamino, nitro, S(O)₂NR^(b)R^(b), —NR^(b)S(O)₂R^(b) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino,cyano or —S(O)_(p)R^(d); R^(b) is independently selected from the groupconsisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylheteroarylalkyl, heterocyclyl and heterocyclylalkyl; R^(c) is selectedfrom hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; R^(d) isselected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and pis 0, 1 or
 2. 6. A compound of formula (I) as claimed in claim 1 or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein X is selected from


7. A compound of formula (I) as claimed in claim 1 or its tautomers,polymorphs, stereoisomers, prodrugs, solvate or a pharmaceuticallyacceptable salts thereof, wherein B is selected from


8. A compound of formula (I) as claimed in claim 1 or its tautomers,polymorphs, stereoisomers, prodrugs, solvate or a pharmaceuticallyacceptable salts thereof, wherein A is selected from


9. A compound of formula (I) as claimed in claim 1 or its tautomers,polymorphs, stereoisomers, prodrugs, solvate or a pharmaceuticallyacceptable salts thereof, wherein Y is selected from N or CR; R isselected from H, hydroxy, alkoxy, alkyl, or aryl; R¹ is alkyl whereinalkyl is unsubstituted or substituted independently with alkoxy, acyl,acylamino, acyloxy, cyano, halogen, hydroxy, carboxy, carboxyalkyl ornitro; R² is selected from a group consisting of hydrogen, halogen,cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, hydroxyalkyl,carboxyalkyl, alkoxy, —NR^(b)R^(b), cycloalkyl, aryl, arylalkyl,aryloxy, heterocyclyl and heteroaryl; wherein alkyl, alkoxy, cycloalkyl,aryl, arylalkyl, heteroaryl, heterocyclyl and R^(b) are unsubstituted orsubstituted independently with alkyl, alkoxy, acyl, acyloxy, nitro,amino, hydroxyamino, alkoxyamino, aminocarbonylamino, cyano, halogen,hydroxy, hydroxyalkyl, carboxy, alkylcarboxy, carboxyalkyl, —SO₃H,aminocarbonyl, cycloalkyl, cycloalkyloxy, aryl, aryloxy, heterocyclyl,heterocyclyloxy, heteroaryl or heteroaryloxy; R³ is selected from agroup consisting of hydrogen, alkyl, aryl and arylalkyl; wherein alkyl,aryl and arylalkyl are unsubstituted or substituted independently withalkyl, acyl, acylamino, acyloxy, amino, cyano, halogen, hydroxy,carboxy, alkylcarboxy or carboxyalkyl; X is an optionally substitutedarylene or an optionally substituted heteroarylene; A is selected from abond, (C₁-C₆)alkylene, (C₂-C₆)alkenylene or (C₂-C₆)alkynylene groupwherein 1 to 4 methylene groups are optionally replaced by groupsindependently selected from O, —S(O)_(p)—, —N(R^(b))—, or —C(O)—; B isselected from hydrogen, heterocyclyl, cycloalkyl, aryl or heteroaryl;wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstitutedor substituted independently with alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino,heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl,carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,alkylcarboxyalkyloxy —SO₃H, aryl, arylalkyl, aryloxy, cycloalkyloxy,heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino,alkoxyamino, nitro, S(O)₂NR^(b)R^(b), —NR^(b)S(O)₂R^(b) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl,halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or—S(O)_(p)R^(c); R^(b) is independently selected from the groupconsisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylheteroarylalkyl, heterocyclyl and heterocyclylalkyl; R^(c) is selectedfrom hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; R^(d) isselected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and pis 0, 1 or
 2. 10. A compound of formula (I) as claimed in claim 1 or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, wherein Y is N; R¹ is alkyl,wherein one or more methylene groups are replaced by hetero atoms orgroups such as —O—, —S(O)p-, —N(R^(a))—, or —C(O) provided heteroatom isnot adjacent to N in the ring; p is selected from 0, 1 or 2; whereinalkyl is unsubstituted or substituted independently with alkoxy, acyl,acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl,alkoxycarbonylamino, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl,thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SO₃H,aminocarbonylamino, hydroxyamino, alkoxyamino, —S(O)₂NR^(a)R^(a),—NR^(a)S(O)₂R^(a), or —S(O)_(p)R^(a); R² is selected from a groupconsisting of hydrogen, halogen, cyano, nitro, carboxy, acyl,aminocarbonyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxyalkyl,haloalkyl, haloalkyloxy, alkoxy, —NR^(b)R^(b), —S(O)_(p)R^(b),cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl,heteroarylalkyl and heteroaryloxy; wherein alkyl, alkenyl, alkynyl,alkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl,arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,heteroaryl, heteroarylalkyl, heteroaryloxy and R^(b) are unsubstitutedor substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl,acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino,hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen,hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy,carboxyalkyl, —SO₃H, arylamino, cycloalkylamino, heteroarylamino,heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl,cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy,heterocyclyl, heterocyclyloxy, —S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl,haloalkoxy, amino, substituted amino, cyano or —S(O)_(p)R^(d); R³ isselected from a group consisting of hydrogen, alkyl and arylalkyl; X isoptionally substituted heteroarylene; A is selected from(C₁-C₆)alkylene, (C₂-C₆)alkenylene or (C₂-C₆)alkynylene group wherein 1to 4 methylene groups are optionally replaced by groups independentlyselected from O, —S(O)_(p)—, —N(R^(b))—, or —C(O)—; wherein alkylene,alkenylene, and alkynylene are unsubstituted or substitutedindependently with alkyl, alkoxy, cycloalkyl, halogen, hydroxy,hydroxyalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,—SO₃H, hydroxyamino, alkoxyamino, S(O)₂NR^(c)R^(c), —NR^(c)S(O)₂R^(c) or—S(O)_(p)R^(d); B is selected from heterocyclyl, cycloalkyl, aryl orheteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl areunsubstituted or substituted independently with alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino,acyloxy, amino, monoalkylamino, dialkylamino, arylamino,cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto,thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy,alkylcarboxyalkyloxy —SO₃H, aryl, arylalkyl, aryloxy, cycloalkyloxy,heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino,alkoxyamino, nitro, S(O)₂NR^(b)R^(b), —NR^(b)S(O)₂R^(b) or—S(O)_(p)R^(d); wherein each substituent is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl,halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or—S(O)_(p)R^(d); R^(a) is independently selected from the groupconsisting of hydrogen and alkyl; R^(b) is independently selected fromthe group consisting of hydrogen, alkyl, acyl, carboxyalkyl,carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylheteroarylalkyl, heterocyclyl and heterocyclylalkyl; R^(c) is selectedfrom hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; R^(d) isselected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and pis 0, 1 or
 2. 11. A compound of formula (I) as claimed in claim 1 or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, which is8-(4-Benzyloxy-phenyl)-1-propyl-1,7-dihydro-purin-6-one,1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,8-[1-(2,3-Difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,1-Propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,1-Propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one,2-Chloro-8-[1-(3-fluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,8-[1-(2,4-Difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one,8-{4-[5-Oxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-ylmethoxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one,1-Propyl-8-{4-[3-(3-trifluoromethyl-phenyl)-prop-2-ynyloxy]-phenyl}-1,7-dihydro-purin-6-one,8-{4-[5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethoxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-8-[1-(2,4-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,8-[1-(3-Fluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Morpholin-4-yl-1-propyl-8-[1-(4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,N-(4-Cyano-phenyl)-2-[4-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetamide,[4-(6-Oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-phenoxy]-acetic acid,8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one,8-(4-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethoxy}-phenyl)-1-propyl-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-(3-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-2-[2-(4-methoxy-phenyl)-ethylamino]-1-propyl-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-2-phenethylamino-1-propyl-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-2-(4-methyl-piperazin-1-yl)-1-propyl-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-2-piperidin-1-yl-1-propyl-1,7-dihydro-purin-6-one,8-{1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one,8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(2-hydroxy-ethylamino)-1-propyl-1,7-dihydro-purin-6-one,2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one,[8-(1-Benzyl-1H-pyrazol-4-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-ylamino]-aceticacid ethyl ester,8-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one,1,2-Dipropyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,2-(3-Fluoro-phenyl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Dimethylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carbonitrile,8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carboxylicacid,8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,8-(4-Methoxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,2-Ethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Benzyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-aceticacid,(S)-1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylicacid,1-Propyl-2-pyrrolidin-1-yl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Methylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Cyclobutylamino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-7-methyl-1-propyl-1,7-dihydro-purin-6-one,2-Methoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile,2-Cyclopentyloxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylicacid amide,{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-aceticacid ethyl ester,2-Morpholin-4-yl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-aceticacid,8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one,(S)-1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylic acid amide,1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-piperidine-3-carboxylicacid,1-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-piperidine-4-carboxylicacid,(2R,4R)-4-Hydroxy-1-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-pyrrolidine-2-carboxylicacid,2-(2,3-Dihydroxy-propylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-(2-Methoxy-ethylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-(4-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-(3-Hydroxy-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-{6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-ethanesulfonicacid,2-(3-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,(Methyl-{6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yl}-amino)-aceticacid,2-(2-Hydroxy-ethylamino)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-(4-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-(4-Hydroxymethyl-piperidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,(S)-3-Methyl-2-[6-oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino]-butyricacid,2-((S)-2-Methoxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-((R)-3-Hydroxy-pyrrolidin-1-yl)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,1-Propyl-2-(tetrahydro-pyran-4-ylamino)-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Fluoro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,1-Propyl-2-(2,2,2-trifluoro-ethoxy)-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-(2-Methoxy-ethoxy)-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,7-Methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Chloro-1-propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one,2-Chloro-8-[6-(3-fluoro-benzylamino)-pyridin-3-yl]-1-propyl-1,7-dihydro-purin-6-one,1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-1,7-dihydro-purin-6-one,1-Propyl-8-(1-pyridin-3-ylmethyl-1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one,1-Propyl-8-[1-(6-trifluoromethyl-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Cyclopropyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,1-Propyl-2-trifluoromethyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-Isobutylamino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one,2-[2-(4-Methoxy-phenyl)-ethylamino]-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-(4-Methyl-piperazin-1-yl)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,1-[8-(1-Methyl-1H-pyrazol-4-yl)-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-yl]-pyrrolidine-2-carboxylicacid methyl ester,2-Benzyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-(3-Fluoro-phenyl)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one,8-(1-Methyl-1H-pyrazol-4-yl)-2-phenethylamino-1-propyl-1,7-dihydro-purin-6-one,8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-(4-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,2-Cyclopropylamino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-(3-Fluoro-phenoxy)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-(4-Methoxy-phenylamino)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,7-Benzyl-2-chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,9-Benzyl-2-chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,9-dihydro-purin-6-one,2-Amino-7-benzyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-8-furan-2-yl-1-propyl-1,7-dihydro-purin-6-one,2-Amino-8-[1-(4-fluoro-benzyl)-1H-imidazo[1,2-b]pyrazol-7-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-8-[1-(4-fluoro-benzyl)-1H-imidazo[1,2-b]pyrazol-7-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Amino-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-Amino-7-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,2-Amino-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,9-dihydro-purin-6-one,7-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,9-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,9-dihydro-purin-6-one,2-Amino-8-furan-2-yl-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-8-furan-2-yl-7-methyl-1-propyl-1,7-dihydro-purin-6-one,8-(1-Methyl-1H-pyrazol-4-yl)-1-propyl-2-(3-trifluoromethyl-benzylamino)-1,7-dihydro-purin-6-one,2-Furan-2-yl-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one,8-(1-Benzyl-1H-pyrazol-4-yl)-2-furan-2-yl-1-propyl-1,7-dihydro-purin-6-one,2-Chloro-8-(6-chloro-pyridin-3-yl)-1-propyl-1,7-dihydro-purin-6-one,2-Difluoromethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Fluoromethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Fluoromethyl-8-{1-[3-(3-methoxy-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one,2-Difluoromethyl-8-{1-[2-oxo-2-(4-m-tolyl-piperazin-1-yl)-ethyl]-1H-pyrazol-4-yl}-1-propyl-1,7-dihydro-purin-6-one,3-Fluoro-N-methyl-N-[5-(6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-benzamide,N-[5-(2-Difluoromethyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-N-methyl-benzamide,N-[5-(2-Difluoromethyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,2-Fluoromethyl-1-propyl-8-[1-(5-trifluoromethyl-pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Fluoromethyl-1-propyl-8-[1-(2-trifluoromethyl-pyridin-4-ylmethyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Fluoromethyl-8-[3-(3-methoxy-phenoxy)-isoxazol-5-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Difluoromethyl-8-{3-[3-(3-fluoro-phenyl)-prop-2-ynyloxy]-isoxazol-5-yl}-1-propyl-1,7-dihydro-purin-6-one,2-Fluoromethyl-1-(2-hydroxy-ethyl)-8-[3-(3-methoxy-phenoxy)-isoxazol-5-yl]-1,7-dihydro-purin-6-one,2-Difluoromethyl-1-ethyl-8-{3-[3-(3-fluoro-phenyl)-prop-2-ynyloxy]-isoxazol-5-yl}-1,7-dihydro-purin-6-one,2-Difluoromethyl-1-ethyl-8-(1-{2-[4-(3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one,1-Ethyl-8-(1-{2-[4-(3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile,N-[5-(2-Cyano-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,N-{5-[2-Cyano-1-(2-hydroxy-ethyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]-pyridin-2-yl}-3-methoxy-benzenesulfonamide,2-Difluoromethyl-1-ethyl-8-{4-[3-(3-methoxy-phenyl)-prop-2-ynyloxy]-phenyl}-1,7-dihydro-purin-6-one,2-Difluoromethyl-1-ethyl-8-{4-[1-(3-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-phenyl}-1,7-dihydro-purin-6-one,2-Difluoromethyl-8-[5-(3-methoxy-phenoxy)-1-methyl-1H-pyrazol-3-yl]-1-propyl-1,7-dihydro-purin-6-one,2-Difluoromethyl-8-{5-[1-(3-methoxy-phenyl)-piperidin-4-yloxy]-1-methyl-1H-pyrazol-3-yl}-1-propyl-1,7-dihydro-purin-6-one,2-Fluoromethyl-8-{3-[1-(3-fluoro-phenyl)-piperidin-4-yloxy]-isoxazol-5-yl}-1-propyl-1,7-dihydro-purin-6-one,1-Ethyl-8-{6-[1-(3-fluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-pyridin-3-yl}-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile,1-Ethyl-8-{6-[1-(3-methoxy-phenyl)-pyrrolidin-3-yloxy]-pyridin-3-yl}-6-oxo-6,7-dihydro-1H-purine-2-carbonitrile,3-[4-(2-Difluoromethyl-1-ethyl-6-oxo-6,7-dihydro-1H-purin-8-yl)-pyrazol-1-ylmethyl]-benzoicacid,2-Difluoromethyl-1-ethyl-8-[1-(3-hydroxymethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,2-Difluoromethyl-3-ethyl-6-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,N-[5-(2-Cyano-4-oxo-3-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,2-Fluoromethyl-6-{3-[1-(3-fluoro-phenyl)-piperidin-4-yloxy]-isoxazol-5-yl}-3-propyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,2-Difluoromethyl-6-{5-[1-(3-methoxy-phenyl)-piperidin-4-yloxy]-1-methyl-1H-pyrazol-3-yl}-3-propyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,3-Ethyl-6-{6-[1-(3-methoxy-phenyl)-pyrrolidin-3-yloxy]-pyridin-3-yl}-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-carbonitrile,2-Fluoromethyl-6-{3-[1-(3-fluoro-phenyl)-piperidin-4-yloxy]-isoxazol-5-yl}-7-hydroxy-3-propyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,2-Difluoromethyl-3-ethyl-6-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-7-methyl-3,5-dihydro-pyrrolo[3,2-d]pyrimidin-4-one,2-Difluoromethyl-1-ethyl-8-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-7-methyl-1,7-dihydro-purin-6-one,N-[5-(2-Cyano-7-methyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyridin-2-yl]-3-methoxy-benzenesulfonamide,1-(2,2-Difluoro-ethyl)-2-ethyl-8-[1-(3-methoxy-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one,3-{3-[4-(2-Difluoromethyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzoicacid,3-(3-{4-[1-(2,2-Difluoro-ethyl)-2-ethyl-6-oxo-6,7-dihydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzoicacid,3-{3-[4-(6-oxo-1-propyl-2-trifluoromethyl-6,7-dihydro-1H-purin-8-yl)-pyrazol-1-yl]-prop-1-ynyl}-benzoicacid, or6-Oxo-1-propyl-8-[6-(3-trifluoromethyl-benzyl)-pyridin-3-yl]-6,7-dihydro-1H-purine-2-carbonitrile.12. A pharmaceutical composition comprising, as an active ingredient, atleast one compound of formula (I), as claimed in claim 1, or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, together with one or morepharmaceutically acceptable carriers or excipients.
 13. A compound offormula (I) as claimed in claim 1, or its tautomers, polymorphs,stereoisomers, prodrugs, solvate or a pharmaceutically acceptable saltsthereof, for treating disease or disorder susceptible to improvement byantagonism of A_(2B) receptor.
 14. A compound of formula (I) as claimedin claim 1, or its tautomers, polymorphs, stereoisomers, prodrugs,solvate or a pharmaceutically acceptable salts thereof, for treatingdisease or disorder susceptible to improvement by antagonism of A_(2A)receptor.
 15. A compound of formula (I), as claimed in claim 1, or itstautomers, polymorphs, stereoisomers, prodrugs, solvate or apharmaceutically acceptable salts thereof, which are adenosine A_(2A)and A_(2B) antagonist, or adenosine A₁ and A_(2B) antagonist, or A₁,A_(2A) and A_(2B) antagonist thereby providing dual or pan antagonisticactivity through additive or/and synergistic effect.
 16. A compound offormula (I), as claimed in claim 1, or its tautomers, polymorphs,stereoisomers, prodrugs, solvate or a pharmaceutically acceptable saltsthereof, for treating asthma, chronic obstructive pulmonary disorder,angiogenesis, pulmonary fibrosis, emphysema, allergic diseases,inflammation, reperfusion injury, myocardial ischemia, atherosclerosis,hypertension, congestive heart failure, retinopathy, diabetes mellitus,obesity, inflammatory gastrointestinal tract disorders, autoimmunediseases, Parkinson's disease, Alzheimer's disease, restless legsyndrome, nocturnal myoclonus, cerebral ischaemia, Huntington's disease,Wilson's disease, multiple system atrophy and/or corticobasaldegeneration.
 17. A compound of formula (I) as claimed in claim 1 foruse in treatment of conditions mediated by adenosine receptor.
 18. Apharmaceutical composition comprising, a compound of formula I asclaimed in claim 1, or its tautomers, polymorphs, stereoisomers,prodrugs, solvate or a pharmaceutically acceptable salts thereof, incombination with one or more therapeutically active agents.
 19. Thepharmaceutical composition as claimed in claim 18 wherein, thetherapeutically active agent is selected from anti-inflammatory agent,anti-diabetic agent, anti-hypertensive agent or anti-dyslipidemic agent.20. The pharmaceutical composition as claimed in claim 18, wherein thepharmaceutically acceptable therapeutically active agent is selectedfrom anticholinergic agent, antimuscarinic agent, steroid, LTB4(leukotriene B4) antagonist, dopamine receptor agonists,phosphodiesterase 4 inhibitor, beta-2 adrenergic receptor agonist,insulin, insulin derivatives and mimetics, insulin secretagogues,insulinotropic sulfonylurea receptor ligands, thiazolidone derivatives,glycogen synthase kinase-3 inhibitor, sodium-dependent glucoseco-transporter inhibitor, glycogen phosphorylase A inhibitor, biguanide,alpha-glucosidase inhibitor, glucagon like peptide-1 (GLP-1), GLP-1analogs and GLP-1 mimetics, modulators of peroxisomeproliferator-activated receptors, dipeptidyl peptidase IV inhibitor,stearoyl-CoA desaturase-1 inhibitor, diacylglycerol acyltransferase 1and 2 inhibitor, acetyl CoA carboxylase 2 inhibitor, and breakers ofadvanced glycation end products, loop diuretics, angiotensin convertingenzyme inhibitor, inhibitor of the Na—K-ATPase membrane pump such asdigoxin, neutralendopeptidase (NEP) inhibitor, ACE/NEP inhibitors,angiotensin II antagonists, renin inhibitors, β-adrenergic receptorblockers, inotropic agents, calcium channel blockers, aldosteronereceptor antagonists, and aldosterone synthase inhibitors,3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, HDLincreasing compounds such as cholesterol ester transfer proteininhibitor, squalene synthase inhibitor, farnesoid X receptor and liver Xreceptor ligand, cholestyramine, fibrates, nicotinic acid, or aspirin.21. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula I as claimed in claim 1, for thetreatment of Parkinson's disease either alone or in a combination withanother pharmaceutically acceptable therapeutically active agent. 22.The pharmaceutical composition as claimed in claim 21, wherein thepharmaceutically acceptable therapeutically active agent is selectedfrom L-DOPA, dopaminergic agonists, MAO-B inhibitors, DOPA decarboxylaseinhibitors or catechol-O-methyltransferase (COMT) inhibitors.
 23. Apharmaceutical composition comprising a therapeutically effective amountof a compound of formula II, for the treatment of Parkinson's diseaseeither alone or in a combination with another pharmaceuticallyacceptable therapeutically active agent.
 24. The pharmaceuticalcomposition as claimed in claim 23, wherein the pharmaceuticallyacceptable therapeutically active agent is selected from L-DOPA,dopaminergic agonists, MAO-B inhibitors, DOPA decarboxylase inhibitorsor catechol-O-methyltransferase (COMT) inhibitors.
 25. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I as claimed in claim 1, for the treatment of cancers of thelung, liver, breast, pancreas, thyroid, skin, central nervous system,larynx, gastrointestine, colon, rectum, bladder, vascular endothelium,esophagus, colorectal, renal, prostate, cervical, ovaries, andendometrial, melanoma, squamous cell or basal cell carcinoma.
 26. Apharmaceutical composition comprising a therapeutically effective amountof a compound of formula II, for the treatment of cancers of the lung,liver, breast, pancreas, thyroid, skin, central nervous system, larynx,gastrointestine, colon, rectum, bladder, vascular endothelium,esophagus, colorectal, renal, prostate, cervical, ovaries, andendometrial, melanoma, squamous cell or basal cell carcinoma.
 27. Apharmaceutical composition comprising a therapeutically effective amountof a compound of formula II, or its tautomers, polymorphs,stereoisomers, prodrugs, solvate or a pharmaceutically acceptable saltsthereof, for the treatment of asthma, chronic obstructive pulmonarydisorder, angiogenesis, pulmonary fibrosis, emphysema, allergicdiseases, inflammation, reperfusion injury, myocardial ischemia,atherosclerosis, hypertension, congestive heart failure, retinopathy,diabetes mellitus, obesity, inflammatory gastrointestinal tractdisorders, autoimmune diseases, Parkinson's disease, Alzheimer'sdisease, restless leg syndrome, nocturnal myoclonus, cerebral ischaemia,Huntington's disease, Wilson's disease, multiple system atrophy and/orcorticobasal degeneration.
 28. A pharmaceutical composition comprising acompound of formula II, or its tautomers, polymorphs, stereoisomers,prodrugs, solvate or a pharmaceutically acceptable salts thereof, incombination with one or more pharmaceutically acceptable therapeuticallyactive agent.
 29. The pharmaceutical composition as claimed in claim 28wherein, the pharmaceutically acceptable therapeutically active agent isselected from anti-inflammatory agent, anti-diabetic agent,anti-hypertensive agent or anti-dyslipidemic agent.
 30. Thepharmaceutical composition as claimed in claim 28, wherein thepharmaceutically acceptable therapeutically active agent is selectedfrom anticholinergic agent, antimuscarinic agent, steroid, LTB4(leukotriene B4) antagonist, dopamine receptor agonists,phosphodiesterase 4 inhibitor, beta-2 adrenergic receptor agonist,insulin, insulin derivatives and mimetics, insulin secretagogues,insulinotropic sulfonylurea receptor ligands, thiazolidone derivatives,glycogen synthase kinase-3 inhibitor, sodium-dependent glucoseco-transporter inhibitor, glycogen phosphorylase A inhibitor, biguanide,alpha-glucosidase inhibitor, glucagon like peptide-1 (GLP-1), GLP-1analogs and GLP-1 mimetics, modulators of peroxisomeproliferator-activated receptors, dipeptidyl peptidase IV inhibitor,stearoyl-CoA desaturase-1 inhibitor, diacylglycerol acyltransferase 1and 2 inhibitor, acetyl CoA carboxylase 2 inhibitor, and breakers ofadvanced glycation end products, loop diuretics, angiotensin convertingenzyme inhibitor, inhibitor of the Na—K-ATPase membrane pump such asdigoxin, neutralendopeptidase (NEP) inhibitor, ACE/NEP inhibitors,angiotensin II antagonists, renin inhibitors, β-adrenergic receptorblockers, inotropic agents, calcium channel blockers, aldosteronereceptor antagonists, and aldosterone synthase inhibitors,3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, HDLincreasing compounds such as cholesterol ester transfer proteininhibitor, squalene synthase inhibitor, farnesoid X receptor and liver Xreceptor ligand, cholestyramine, fibrates, nicotinic acid, or aspirin.31. A process for the preparation of a compound of formula (I) asclaimed in claim 1, or its tautomers, polymorphs, stereoisomers,prodrugs, solvate or a pharmaceutically acceptable salts thereof, saidprocess comprising: reacting a diamine of formula (III)

with an acid of formula (IV) or its acid chloride

to obtain a compound of formula (V);

converting compound of formula (V) to a compound of formula (I); and

optionally reacting the above compound of formula (I) with R³-Hal toprovide compounds of formula (I).


32. A process for the preparation of a compound of formula (I) asclaimed in claim 1, or its tautomers, polymorphs, stereoisomers,prodrugs, solvate or a pharmaceutically acceptable salts thereof, saidprocess comprising: reacting a diamine of formula (III)

with an acid of formula (VI) or its acid chloride

to obtain a compound of formula (VII);

reacting compound of formula (VII) with a compound PG₁ to obtain acompound of formula (VIII);

wherein PG and PG₁ are independently selected protecting groups; andreacting compound of formula (VIII) with a compounds of formula (IX)L₁-A-B  (IX) to obtain a compound of formula (I);

optionally reacting the above compound of formula (I) with R³-Hal toprovide compound of formula (I)